INDAZOLE INHIBITORS OF THE WNT SIGNAL PATHWAY AND USES THEREOF

INHIBITEURS D'INDAZOLE DE PARCOURS DE SIGNAL WNT ET LEURS UTILISATIONS

English Abstract

Indazole compounds of Formula (I) are disclosed:more particularly,
the present invention concerns the use of an indazole compound or analogs
thereof, for the modulation of cellular events mediated by Wnt pathway
signaling.
(see above formula)

French Abstract

L'invention concerne des composés d'indazole pour traiter diverses maladies et pathologies. Plus particulièrement, la présente invention concerne l'utilisation d'un composé d'indazole ou d'analogues de celui-ci, dans le traitement de troubles caractérisés par l'activation d'une signalisation de trajet de Wnt (par exemple, un cancer, une prolifération cellulaire anormale, une angiogenèse, la maladie d'Alzheimer, une maladie pulmonaire et l'arthrose), la modulation d'évènements cellulaires arbitrés par la signalisation de trajet de Wnt, ainsi que de maladies génétiques et d'états/troubles/maladies neurologiques dus à des mutations ou à un dérèglement du trajet de Wnt et/ou d'un ou plusieurs des composants de signalisation de Wnt. L'invention concerne également des procédés de traitement d'états de maladie associés au Wnt. Un mode de réalisation décrit dans la présente invention comprend un composé ayant la structure de la formule I.

Claims

CLAIMS:
1. A compound or pharmaceutically acceptable salt thereof having the
structure
of Formula I:
<IMG>
wherein:
R1 is ¨heteroarylR3R4;
R2 is selected from the group consisting of H, pyridin-2-ylR5, pyridin-4-ylR5,
thiopheneR5, furanR5, imidazoleR5, -heterocyclylR6, and ¨arylR7;
R3 is selected from the group consisting of H, -heterocyclylR8, ¨NHC(=O)R9,
¨NHSO 2R10, -NR 11R12, and -(C1-6alkyl)NR 11R12;
with the proviso that R2 and R3 are not both H;
R4 is 1-3 substituents each selected from the group consisting of H, C1-9
alkyl,
halide, -CF 3, -CN, OR 13, and amino;
each R5 is independently 1-4 substituents each selected from the group
consisting of H, C1-9alkyl, halide, -CF 3, -CN, OR 13, -C(=O)R11, amino, and
-(C1-6alkyl)NR 11R12;
each R6 is independently 1 -5 substituents each selected from the group
consisting of H, C1-9 alkyl, halide, -CF 3, -CN, OR 13, and amino;
147

each R7 is independently 1-5 substituents each selected from the group
consisting of C1-9 alkyl, halide, -CF 3, -CN, OR 13, amino, ¨(C1-6 alkyl)NHSO
2R11,
-NR 12(C1-6 alkyl)NR 11R12, and -(C1-6 alkyl)NR 11R12;
R8 is 1-5 substituents each selected from the group consisting of H, C1-9
alkyl,
halide, -CF 3, -CN, OR 13, and amino;
R9 is selected from the group consisting of C1-9 alkyl, ¨heteroarylR5,
-heterocyclylR6, ¨arylR7, and ¨CH2carbocyclyl;
R10 is selected from the group consisting of C1-9 alkyl, ¨heteroarylR5,
-heterocyclylR6, ¨arylR7, and ¨carbocyclylR14;
each R11 is independently selected from C1-6 alkyl;
each R12 is independently selected from the group consisting of H and C1-6
alkyl;
each R11 and R12 are optionally linked together with the nitrogen to which
they
are bound to form a substituted or unsubstituted five or six membered
heterocyclyl ring:
each R13 is independently selected from the group consisting of H and C1-6
alkyl;
R14 is 1-5 substituents each selected from the group consisting of H, C1-9
alkyl,
halide, -CF 3, -CN, OR 13 and amino.
2. The compound of claim 1, or pharmaceutically acceptable salt thereof,
wherein
R1 is pyridineR3R4.
3. The compound of claim 2, or pharmaceutically acceptable salt thereof,
wherein
R1 is pyridin-3-ylR3R4.
4. The compound of claim 3, or pharmaceutically acceptable salt thereof,
wherein
R3 is -(C1-6 alkyl)NR 11R12.
148

5. The compound of claim 4, or pharmaceutically acceptable salt
thereof, wherein
R3 is -(C1-2 alkyl)NR 11R12, R11 is -(C1-2 alkyl), R12 is -(C1-2 alkyl) and R4
is H.
6. The compound of claim 4, or pharmaceutically acceptable salt
thereof, wherein
R11 and R12 are optionally linked together with the nitrogen to which they are
bound to form a
substituted or unsubstituted five or six membered heterocyclyl ring and R4 is
H.
7. The compound of claim 6, or pharmaceutically acceptable salt
thereof, wherein
the five or six membered heterocyclyl ring is substituted with 1-2 fluorines.
8. The compound of claim 3, or pharmaceutically acceptable salt
thereof, wherein
R3 is ¨NHC(=O)R9.
9. The compound of claim 8, or pharmaceutically acceptable salt
thereof, wherein
R4 is H and R9 is selected from the group consisting of -(C2-5 alkyl), phenyl,
¨carbocyclyl and
¨CH 2carbocyclyl.
10. The compound of claim 3, or pharmaceutically acceptable salt
thereof, wherein
R3 is ¨NHSO 2R10.
11. The compound of claim 10, or pharmaceutically acceptable salt
thereof,
wherein R4 is H and R10 is selected from the group consisting of ¨(C1-4 alkyl)
and phenyl.
12. The compound of claim 3, or pharmaceutically acceptable salt
thereof, wherein
R3 is ¨heterocyclylR8.
13. The compound of claim 12, or pharmaceutically acceptable salt
thereof,
wherein R4 is H and heterocyclyl is selected from the group consisting of
morpholine,
piperazine and piperidine.
14. The compound of claim 3, or pharmaceutically acceptable salt
thereof, wherein
R3 is H and R4 is amino.
15. The compound according to any one of claims 3-14, or
pharmaceutically
acceptable salt thereof, in which R2 is -pyridin-2-ylR5.
149

16. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is -pyridin-4-ylR5.
17. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is thiopheneR5.
18. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is ¨heterocyclylR6.
19. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is ¨heterocyclylR6, in which R6 is
selected from the group
consisting of H, F and ¨(C1-4alkyl), and heterocyclyl is selected from the
group consisting of
morpholine, piperazine and piperidine.
20. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is ¨arylR7.
21. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is ¨phenylR7 and R7 is 1-2 fluorine
atoms.
22. The compound according to any one of claims 3-14, or pharmaceutically
acceptable salt thereof, in which R2 is ¨phenylR7 and R7 is 2 substituents
consisting of 1
fluorine atom and either -NR 12(C1-6alkyl)NR 11R12 or -(C1-6alkyl)NHSO 2R11.
23. The compound:
150

<IMG>
151

<IMG>
152

<IMG>
153

<IMG>
154

<IMG>
155

<IMG>
156

<IMG>
157

<IMG>
158

<IMG>
159

<IMG>
160

<IMG>
161

<IMG>
162

<IMG>
163

<IMG>
164

<IMG>
165

<IMG>
166

<IMG>
167

<IMG>
168

<IMG>
169

<IMG>
170

<IMG>
or pharmaceutically acceptable salt thereof.
24. The compound:
171

<IMG>
172

<IMG>
173

<IMG>
174

or pharmaceutically acceptable salt thereof.
25. The compound:
<IMG>
175

<IMG>
or pharmaceutically acceptable salt thereof.
26. A
compound, or pharmaceutically acceptable salt thereof, having the structure
of Formula I:
<IMG>
wherein:
R1 is -heteroarylR3R4;
R2 is -arylR7;
R3 is a -NHC(=O)R9;
R4 is H;
176

each R7 is independently 1-2 substituents each selected from the group
consisting of halide, -CF3, -CN, -(C1-6 alkyl)NHSO2R11, -(C1-6 alkyl)NR11R12,
and
-NR12(C1-6alkyl)NR11R12;
R9 is selected from the group consisting of -(C1-6alkyl), -aryl, -carbocyclyl,
and -CH2carbocyclyl;
each R11 is independently selected from -(C1-6alkyl);
each R12 is independently selected from the group consisting of H and
-(C1-6alkyl); and
each R11 and R12 are optionally linked together with the nitrogen to which
they
are bound to form a four to six membered heterocyclyl ring.
27. The compound of claim 26, or pharmaceutically acceptable salt thereof,
wherein R1 is pyridinylR3R4.
28. The compound of claim 26 or 27, or pharmaceutically acceptable salt
thereof,
wherein R1 is pyridin-3-ylR3R4.
29. The compound of any one of claims 26-28, or pharmaceutically acceptable
salt
thereof, wherein R9 is -(C1-6alkyl).
30. The compound of any one of claims 26-28, or pharmaceutically acceptable
salt thereof, wherein R9 is -(C2-5alkyl).
31. The compound of any one of claims 26-28, or pharmaceutically acceptable
salt thereof, wherein R9 is carbocyclyl.
32. The compound of any one of claims 26-28, or pharmaceutically acceptable
salt thereof, wherein R9 is -CH2carbocyclyl.
33. The compound of any one of claims 26-28, or pharmaceutically acceptable
salt thereof, wherein R9 is phenyl.
177

34. The compound of any one of claims 26-33, or pharmaceutically acceptable
salt
thereof, wherein R7 is halide.
35. The compound of any one of claims 26-34, or pharmaceutically acceptable
salt
thereof, wherein R7 is fluorine.
36. The compound of any one of the claims 26-33, or pharmaceutically
acceptable
salt thereof, wherein R7 is 2 substituents consisting of a fluorine atom and
-(C1-6 alkyl)NR11R12.
37. The compound of any one of claims 26-33 and 36, or pharmaceutically
acceptable salt thereof, wherein R11 and R12 are both -(C1-2 alkyl).
38. The compound of any one of claims 26-33 and 36, or pharmaceutically
acceptable salt thereof, wherein R11 and R12 are linked to form an azetidine
ring.
39. The compound of any one of claims 26-33 and 36, or pharmaceutically
acceptable salt thereof, wherein R11 and R12 are linked to form a pyrrolidine
ring
40. The compound of any one of claims 26-33 and 36, or pharmaceutically
acceptable salt thereof, wherein R11 and R12 are linked to form a piperidine
ring.
41. The compound of any one of claims 26-33, or pharmaceutically acceptable
salt
thereof, wherein R7 is 2 substituents consisting of a fluorine atom and
-NR12(C1-6 alkyl)NR11R12.
42. The compound of any one of claims 26-33 and 41, or pharmaceutically
acceptable salt thereof, wherein R7 is 2 substituents consisting of a fluorine
atom and
-NHCH2CH2NR11R12.
43. The compound of any one of claims 26-33, 41 and 42, or pharmaceutically
acceptable salt thereof, wherein R11 and R12 are both -(C1-2alkyl).
44. The compound of any one of claims 26-33, or pharmaceutically acceptable
salt
thereof, wherein R7 is 2 substituents consisting of a fluorine atom and -(C1-
6alkyl)NHSO2R11.
178

45. The compound of any one of the claims 26-33 and 44, or pharmaceutically
acceptable salt thereof, wherein R7 is 2 substituents consisting of a fluorine
atom and
¨CH2HSO2R11.
46. The compound of any one of claims 26-33, 44 and 45, or pharmaceutically
acceptable salt thereof. wherein R11 is -(C1-2 alkyl).
47. The compound:
<IMG>
179

<IMG>
180

<IMG>
181

<IMG>
182

<IMG>
, or a pharmaceutically acceptable salt thereof.
48. A
compound, or pharmaceutically acceptable salt thereof, having the structure
of Formula I:
<IMG>
wherein:
R1 is ¨pyridin-3-ylR3R4;
R2 is ¨phenylR7;
R3 is a ¨NHC(=O)R9;
R4 is H;
183

each R7 is independently 1-2 substituents each selected from the group
consisting of fluorine, ¨CH2NHSO2R11, -(C1-6 alkyl)NR11R12, and -
NHCH2CH2NR11R12;
R9 is selected from the group consisting of ¨(C2-5 alkyl), ¨phenyl,
¨carbocyclyl,
and ¨CH2carbocyclyl;
each R11 is independently selected from -(C1-2 alkyl);
each R12 is independently selected from the group consisting of H and
-(C1-2 alkyl); and
each R11 and R12 are optionally linked to form a four to six membered
heterocyclyl ring.
49. The compound of claim 48, or pharmaceutically acceptable salt thereof,
wherein R9 is ¨(C2-5 alkyl).
50. The compound of claim 48, or pharmaceutically acceptable salt thereof,
wherein R9 is carbocyclyl.
51. The compound of claim 48, or pharmaceutically acceptable salt thereof,
wherein R7 is one fluorine.
52. The compound of claim 48, or pharmaceutically acceptable salt thereof,
wherein R7 is 2 substituents consisting of a fluorine atom and ¨CH2NHSO2R11,
and R11 is
-(C1-2 alkyl).
53. The compound:
184

<IMG>
or a pharmaceutically acceptable salt thereof.
54. The compound:
<IMG>
or a pharmaceutically acceptable salt thereof.
55. The compound:
<IMG>
or a pharmaceutically acceptable salt thereof.
185

56. The compound:
<IMG>
or a pharmaceutically acceptable salt thereof.
57. The compound:
<IMG>
or a pharmaceutically acceptable salt thereof.
58. A pharmaceutical composition comprising a compound according to any one
of claims 1-57, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically
acceptable excipient.
59. A pharmaceutical composition comprising a compound having a structure
selected from the group consisting of:
186

<IMG>
or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier.
60. The pharmaceutical composition of claim 59, wherein the compound has
a
structure of:
<IMG>
or a pharmaceutically acceptable salt thereof.
61. The pharmaceutical composition of claim 59, wherein the compound has
a
structure of:
187

<IMG>
or a pharmaceutically acceptable salt thereof.
62. The pharmaceutical composition of claim 59, wherein the compound has a
structure of:
<IMG>
or a pharmaceutically acceptable salt thereof.
63. The pharmaceutical composition of claim 59, wherein the compound has a
structure of:
<IMG>
or a pharmaceutically acceptable salt thereof.
64. A compound or pharmaceutically acceptable salt thereof having the
structure
of Formula I:
<IMG>
188

wherein:
R1 is ¨heteroarylR3R4;
R2 is pyridin-3-ylR5;
R3 is selected from the group consisting of -heterocyclylR8, -NR11R12, an , -
(C1-6
alkyl)NR11R12;
R4 is 1-3 substituents each selected from the group consisting of H, C1-9
alkyl, halide,
-CF3, -CN, OR13, and amino;
each R5 is independently 1-4 substituents each selected from the group
consisting of
H, C1-9alkyl, halide, -CF3, -CN, OR13, -C(=O)R11, amino, and -(C1-
6alkyl)NR11R12;
R8 is 1-5 substituents each selected from the group consisting of H, C1-9
alkyl, halide,
-CF3, -CN, OR13, and amino;
each R11 is independently C1-6alkyl, wherein each C1-6alkyl is optionally
substituted
with aryl or carbocyclyl;
each R12 is independently selected from the group consisting of H and
unsubstituted
C1-6 alkyl;
each R11 and R12 are optionally linked to form a five or six membered
heterocyclyl
ring; and
each R13 is independently selected from the group consisting of H and C1-6
alkyl.
65. The compound of claim 64, or pharmaceutically acceptable salt thereof,
wherein R1 is pyridineR3R4.
66. The compound of claim 65, or pharmaceutically acceptable salt thereof,
wherein R1 is pyridin-3-y1R3R4.
67. The compound of claim 66, or pharmaceutically acceptable salt thereof,
wherein R3 is -(C1-6alkyl)NR11R12.
68. The compound of claim 67, or pharmaceutically acceptable salt thereof,
wherein R3 is -(C1-2 alkyl)NR11R12, R11 is -(C1-2 alkyl), R12 is -(C1-2 alkyl)
and R4 is H.
189

69. The compound of claim 67, or pharmaceutically acceptable salt thereof,
wherein R11 and R12 are optionally linked to form a five or six membered
heterocyclyl ring
and R4 is H.
70. The compound of claim 69, or pharmaceutically acceptable salt thereof,
wherein the five or six membered heterocyclyl ring is substituted with 1-2
fluorines.
71. The compound of claim 66, or pharmaceutically acceptable salt thereof,
wherein R3 is ¨heterocyclylR8.
72. The compound of claim 71, or pharmaceutically acceptable salt thereof,
wherein R4 is H and heterocyclyl is selected from the group consisting of
morpholine,
piperazine and piperidine.
73. The compound of claim 66, or pharmaceutically acceptable salt thereof,
wherein R3 is H and R4 is amino.
74. The compound according to any one of claims 65-73, or a
pharmaceutically
acceptable salt thereof, in which R2 is -pyridin-3-ylR5 and R5 is H.
75. The compound according to any one of claims 65-73, or a
pharmaceutically
acceptable salt thereof, in which R2 is -pyridin-3-ylR5 and R5 is 1-2 fluorine
atoms.
76. The compound:
<IMG>
190

<IMG>
or pharmaceutically acceptable salt thereof.
77. A pharmaceutical composition comprising a compound according to any one
of claims 64-76, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically
acceptable excipient.
78. Use of the compound according to any one of claims 1-57 and 64-76, or a
pharmaceutically acceptable salt thereof, for the treatment of a disorder or
disease selected
from the group consisting of cancer, a bone or cartilage disease,
osteoarthritis, lung disease,
pulmonary fibrosis, osteochondrodysplasia, and scleroderma.
79. The use of claim 78, wherein the disorder or disease is cancer.
80. The use of claim 78, wherein the disorder or disease is pulmonary
fibrosis.
81. The use of claim 78, wherein the disorder or disease is
osteochondrodysplasia.
82. The use of claim 78, wherein the disorder or disease is scleroderma.
83. The use of claim 78, wherein the disorder or disease is a bone or
cartilage
disease.
84. The use of claim 78, wherein the disorder or disease is lung disease.
85. The use of claim 78, wherein the disorder or disease is osteoarthritis.
86. The use of claim 79, wherein the cancer is chosen from: hepatocellular
carcinoma, colon cancer, breast cancer, pancreatic cancer, leukemia, lymphoma,
sarcoma, and
ovarian cancer.
87. The use of any one of claims 78 to 86, wherein said use is in a human.
191

88. The use of claim 78, wherein the compound inhibits a kinase activity.
89. Use of the compound according to any one of claims 1-57 and 64-76, or a
pharmaceutically acceptable salt thereof, for treating a disease or disorder
mediated by kinase
activity in a patient.
90. The use of claim 89, wherein the disease or disorder comprises tumor
growth,
cell proliferation, or angiogenesis.
91. Use of the compound according to any one of claims 1-57 and 64-76, or a
pharmaceutically acceptable salt thereof, for inhibiting the activity of a
protein kinase
receptor.
92. The use according to claim 88 or 89, wherein the kinase is selected
from the
CDK, VEGF, CLK, HIPK, Abl, JAK or CHK families of kinases.
93. A method of inhibiting one or more proteins in the Wnt pathway, the
method
comprising contacting a cell in vitro with an effective amount of the compound
according to
any one of claims 1-57 and 64-76, or a pharmaceutically acceptable salt
thereof.
94. The method of claim 93, wherein the cell is a human cell.
95. The method of claim 94, wherein the human cell is a cancerous cell.
96. The method of claim 95, wherein the cancerous cell is a colon cancer
cell.
97. Use of the compound according to any one of claims 1-57 and 64-76, or a
pharmaceutically acceptable salt thereof, for inhibiting one or more kinases.
98. The use of claim 97, wherein the kinase is selected from the CDK, VEGF,
CLK, HIPK, Abl, JAK or CHK families of kinases.
192

Description

CA 02853703 2015-11-09
60412-4774
INDAZOLE INHIBITORS OF THE WNT SIGNAL PATHWAY AND USES THEREOF
Field of the Invention
[00011 This invention further relates to inhibitors of one or more proteins in
the Wnt pathway,
including inhibitors of one or more Wnt proteins, and compositions comprising
the same.
.. [0002] More particularly, it concerns a compound of Formula (I):
N\ -NH
R1
\N
NI/
or pharmaceutically acceptable salt thereof
BACKGROUND OF THE INVENTION
Description of the Related Art
[0003] Pattern formation is the activity by which embryonic cells form ordered
spatial
arrangements of differentiated tissues. Speculation on the mechanisms
underlying these patterning
effects usually centers on the secretion of a signaling molecule that elicits
an appropriate response
from the tissues being patterned. More recent work aimed at the identification
of such signaling
molecules implicates secreted proteins encoded by individual members of a
small number of gene
families.
[00041 A longstanding idea in cancer biology is that cancers arise and grow
due to the formation
of cancer stem cells, which may constitute only a minority of the cells within
a tumor but are
nevertheless critical for its propagation. Stem cells are appealing as the
cell of origin for cancer
because of their pre-existing capacity for self-
1

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renewal and for unlimited replication. In addition, stem cells are relatively
long-lived in
comparison to other cells within tissues, providing a greater opportunity to
accumulate
the multiple additional mutations that may be required to increase the rate of
cell
proliferation and produce clinically significant cancers. Of particular recent
interest in the
origin of cancer is the observation that the Wnt signaling pathway, which has
been
implicated in stem cell self-renewal in normal tissues, upon continuous
activation has
also been associated with the initiation and growth of many types of cancer.
This
pathway thus provides a potential link between the normal self-renewal of stem
cells and
the aberrantly regulated proliferation of cancer stem cells.
[0005] The Wnt
growth factor family includes more than 10 genes identified
in the mouse and at least 7 genes identified in the human. Members of the Wnt
family of
signaling molecules mediate many important short-and long-range patterning
processes
during invertebrate and vertebrate development. The Wnt signaling pathway is
known for
its important role in the inductive interactions that regulate growth and
differentiation,
and likely also plays important roles in the homeostatic maintenance of post-
embryonic
tissue integrity. Wnt stabilizes cytoplasmic p-catenin, which stimulates the
expression of
genes including c-myc, c jun, fra-1, and cyclin Dl. In addition, misregulation
of Wnt
signaling can cause developmental defects and is implicated in the genesis of
several
human cancers. More recently, the Wnt pathway has been implicated in the
maintenance
of stem or progenitor cells in a growing list of adult tissues that now
includes skin, blood,
gut, prostate, muscle and the nervous system.
[0006]
Pathological activation of the Wnt pathway is also believed to be the
initial event leading to colorectal cancer in over 85% of all sporadic cases
in the Western
world. Activation of the Wnt pathway has also been extensively reported for
hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer,
melanomas,
mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of
the Wnt
pathway can be used for stem cell research or for the treatment of any
diseases
characterized by aberrant Wnt activation such as diabetic retinopathy,
pulmonary fibrosis,
rheumatoid arthritis, scleroderma as well as mycotic and viral infections and
bone and
cartilage diseases. As such, it is a therapeutic target that is of great
interest to the field.
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[0007] In addition
to cancer, there are many cases of genetic diseases due to
mutations in Wnt signaling components. Examples of some of the many diseases
are
Alzheimer's disease [Proc. Natl. Acad. Sci. U S A (2007), 104(22), 9434-9],
osteoarthritis, polyposis coli [Science (1991), 253(5020), 665-669], bone
density and
vascular defects in the eye (osteoporosis-pseudoglioma syndrome, OPPG) EN.
Engl.
Med. (2002), 346(20), 1513-21], familial exudative vitreoretinopathy [Hum.
Mutat.
(2005), 26(2), 104-12], retinal angiogenesis [Nat. Genet. (2002), 32(2), 326-
30], early
coronary disease [Science (2007), 315 (5816), 1278-82], tetra-amelia syndrome
[Am. J
Hum. Genet. (2004), 74(3), 558-63], Mtillerian-duct regression and
virilization [Engl. J.
Med (2004), 351(8), 792-81, SERKAL syndrome [Am. J Hum. Genet. (2008), 82(4 39-
47], diabetes mellitus type 2 [Am. J. Hum. Genet. (2004), 75(5), 832-43; N
Engl. I Med
(2006), 355(3), 241-50], Fuhrmann syndrome [Am. I Hum. Genet. (2006), 79(2),
402-8],
Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome [Am. I Hum. Genet.
(2006),
79(2), 402-8], odonto-onycho-dermal dysplasia [Am. I Hum. Genet. (2007),
81(4), 821-
8], obesity [Diabetologia (2006), 49(4), 678-84], split-hand/foot malformation
[Hum.
Mol. Genet. (2008), 17(17), 2644-53], caudal duplication syndrome [Am. J. Hum.
Genet.
(2006), 79(1), 155-62], tooth agenesis [Am. I Hum. Genet. (2004), 74(5), 1043-
50],
Wilms tumor [Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat.
Genet. (2009),
41(1), 95-100], focal dermal hypoplasia [Nat. Genet. (2007), 39(7), 836-8],
autosomal
recessive anonychia [Nat. Genet. (2006), 38(11), 1245-7], neural tube defects
[N Engl.
Med. (2007), 356(14), 1432-7], alpba-thalassemia (ATRX) syndrome [The Journal
of
Neuroscience (2008), 28(47), 12570 -12580], fragile X syndrome [PLoS Genetics
(2010), 6(4), e1000898], ICF syndrome, Angelman syndrome [Brain Research
Bulletin (2002), 57(1), 109-119], Prader-Willi syndrome
[Journal of
Neuroscience (2006), 26(20), 5383-5392], Beckwith-Wiedemann Syndrome
[Pediatric
and Developmental Pathology (2003), 6(4), 299-306] and Rett syndrome.
[0008] Regulation
of cell signaling by the Wnt signaling pathway is critical
for the formation of neuronal circuits. Wnt pathway modulates in neural
tissue, among
other things, axon pathfinding, dendritic development, and synaptic assembly.
Through
different receptors, Wnt pathway activates and/or regulates diverse signaling
pathways
and other processes that lead to local changes on the cytoskeleton or global
cellular
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changes involving nuclear function. Recently, a link between neuronal
activity, essential
for the formation and refinement of neuronal connections, and Wnt signaling
has been
uncovered. Indeed, neuronal activity regulates the release of various Wnt
proteins and the
localization of their receptors. Wnt pathway mediates synaptic structural
changes induced
by neuronal activity or experience. Evidence suggests that dysfunction in Wnt
signaling
contributes to neurological disorders [Brain Research Reviews (2000), 33(1), 1-
12;
Oncogene (2006) 25(57), 7545-7553; Molecular Neurodegeneration (2008), 3, 9;
Neurobiology of Disease (2010), 38(2), 148-153; Journal of Neurodevelopmental
Disorders (2011), 3(2), 162-174 and Cold Spring Harbor Perspectives in Biology
February (2012), 4(2)].
SUMMARY OF THE INVENTION
[0009] The present invention makes available methods and reagents,
involving contacting a cell with an agent, such as an aromatic compound, in a
sufficient
amount to antagonize a Wnt activity, e. g., to reverse or control an aberrant
growth state
or correct a genetic disorder due to mutations in Wnt signaling components.
[0010] Some embodiments disclosed herein include Wnt inhibitors
containing
an indazole core. Other embodiments disclosed herein include pharmaceutical
compositions and methods of treatment using these compounds.
[0011] One embodiment disclosed herein includes a compound having the
structure of Formula 1:
R2 / N
N \ NH
R1
\ N
as well as prodrugs and pharmaceutically acceptable salts thereof.
[0012] In some embodiments of Formula (I):
Rl is ¨heteroary1R3R4;
4

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R2 is selected from the group consisting of H, pyridin-2-y1R5, pyridin-4-y1R5,
thiopheneR5, furanR5, imidazoleR5, -heterocyclyIR6and ¨aryIR7;
R3 is selected from the group consisting of H, -heterocycly1R8, ¨NHC(=0)R9,
¨NHSO7R19, -NR' 'R'2 -(C1.6alkyl)NRH R12;
with the proviso that R2 and R3 are not both H;
Rl is 1-3 substituents each selected from the group consisting of H, C1_,
alkyl, halide,
-CF3, -CN, Ole and amino;
each R5 is independently 1-4 substitucnts each selected from the group
consisting of
H, C1_, alkyl, halide, -CF3, -CN, OR", -C(=0)R11, amino and -
(Ci_6alkyl)NRHR12;
each R6 is independently 1-5 substituents each selected from the group
consisting of
H, C1_, alkyl, halide, -C173, -CN, OR13 and amino;
each R7 is independently 1-5 substituents each selected from the group
consisting of
C,.9 alkyl, halide, -CF3, -CN, OR13, amino, ¨(C1_6alkyl)NHSO2Rii, -N R12(Ci _6
alkyl)NR11R12 and
-(C1.6alkyl)NRI1R12;
8
R is 1-5 substituents each selected from the group consisting of H, CI.,
alkyl, halide,
-CF3, -CN, Ole and amino;
R9 is selected from the group consisting of C1_, alkyl, ¨heteroaryIR5, -
heterocyclylle,
¨arylle and ¨CH2carbocycly1;
R19 is selected from the group consisting of C1.9 alkyl, ¨heteroary1R5, -
heterocyclyIR6,
¨ary1R7, and ¨carbocyclyIR14;
each Ru is independently selected from CI, alkyl;
each R.12 is independently selected from the group consisting of H and CI_O
alkyl;
each R11 and R12 are optionally linked together with the nitrogen to which
they are
bound to form a substituted or unsubstituted five or six membered heterocyclyl
ring;
each R13 is independently selected from the group consisting of H and C,
alkyl;
5

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R" is 1-5 substituents each selected from the group consisting of H, C1.9
alkyl, halide,
-CF3, -CN, OR" and amino.
[0012a] In another embodiment, wherein:
R1 is ¨heteroaryIR3R4;
R2 is ¨ary1R7;
R3 is a ¨NHC(=0)R9;
R4 is H;
each R7 is independently 1-2 substituents each selected from the group
consisting of
halide, -CF3, ¨CN, ¨(Ci_oalkyl)NHSO2R11, -(C1.6 alkyl)NR11R12, and -
NR12(Ci_oalkyl)NR"R12;
R9 is selected from the group consisting of ¨(C1.6 alkyl), ¨aryl,
¨carbocyclyl, and
¨CH2carbocycly1;
each R11 is independently selected from -(C1.6 alkyl);
each R12 is independently selected from the group consisting of H and ¨(C1,6
alkyl);
and
1 5 each R" and R12 are optionally linked to form a four to six
membered heterocycly1
ring.
[0012b] In yet another embodiment, wherein:
R1 is ¨pyridin-3-yIR3R4;
R2 is ¨pheny1R7;
le is a -NHC(=0)R9;
R4 is H;
each R.7 is independently 1-2 substituents each selected from the group
consisting of
fluorine, ¨CH2NHSO)R", -(C1_6alkyl)NR11R12, and -NI ICH,CH,NR I1R12;
6

81778925
R9 is selected from the group consisting of ¨(C2_5alkyl), ¨phenyl,
¨carbocyclyl, and
¨CH2carbocycly1;
each R" is independently selected from -(C1_2alkyl);
each R12 is independently selected from the group consisting of H and
alkyl);
and
each R" and R12 are optionally linked to form a four to six membered
heterocycly1
ring.
[0012c] In yet another embodiment, wherein:
R1 is ¨heteroary1R3R4;
R2 is pyridin-3-y1R5;
R3 is selected from the group consisting of H, -heterocyc1y1R8, -NR11R12, and -
(C1_6
alkyl)NRIIR12;
R4 is 1-3 substituents each selected from the group consisting of H, C1_9
alkyl, halide,
-CF3, -CN, OR", and amino;
each R is independently 1-4 substituents each selected from the group
consisting of H,
alkyl, halide, -CF3, -CN, OR13, -C(=0)R11, amino, and -(Ci_6alkyl)NR11R12;
R8 is 1-5 substituents each selected from the group consisting of H, C1.9
alkyl, halide,
-CF3, -CN, OR13, and amino;
each R11 is independently C16 alkyl, wherein each Ci.6alkyl is optionally
substituted
with aryl or carbocycly1;
each R12 is independently selected from the group consisting of H and
unsubstituted
C16 alkyl;
each R" and R12 are optionally linked to form a five or six membered
heterocyclyl ring; and
each R13 is independently selected from the group consisting of II and C14,
alkyl.
[0013] Some embodiments include stereoisomers and pharmaceutically acceptable
salts of a
compound of general Formula (I).
[0014] Some embodiments include pro-drugs of a compound of general Formula
(I).
[0015] Some embodiments of the present invention include pharmaceutical
compositions comprising
a compound of general Formula (I) and a pharmaceutically acceptable carrier.
7
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81778925
[0016] Other embodiments disclosed herein include methods of inhibiting one or
more members of
the Wnt pathway, including one or more Wnt proteins.
[0017] Another embodiment disclosed herein includes a pharmaceutical
composition that has a
compound according to any of the above formulas and a pharmaceutically
acceptable carrier, diluent,
or excipient.
[0018] Some embodiments of the present invention include methods to prepare a
compound of
general Formula (I).
[0019] It is to be understood that both the foregoing general description and
the following detailed
description are exemplary and explanatory only and are not restrictive of the
invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Compositions and methods for inhibiting one or more members of the Wnt
pathway, including
one or more Wnt proteins would be of tremendous benefit. Certain embodiments
provide such
compositions and methods. Certain related
7a
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compounds and methods are disclosed in U.S. Application Ser. No. 12/8'52,706,
filed
August 9, 2010, which claims priority to U.S. Provisional Application Ser.
Nos.
61/232,603 and 61/305,459.
[0021] Some embodiments relate to a method for treating a disease
such as
cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,
seleroderma,
mycotic and viral infections, osteochondrodysplasia, Alzheimer's di,sease,
lung disease,
osteoarthritis, polyposis coli, osteoporosis-pseudoglioma syndrome, familial
exudative
vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia
syndrome,
Milllerian-duct regression and virilization, SEItKAL syndrome, diabetes
mellitus type 2,
Fuhrmaim syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,
odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal
duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal
dermal
hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-
thalassemia
(ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-
Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome.
[0022] In some embodiments, pharmaceutical compositions are
provided that
are effective for treatment of a disease of an animal, e.g., a mammal, caused
by the
pathological activation or mutations of the Wnt pathway. The composition
includes a
pharmaceutically acceptable carrier and a Wnt pathway inhibitor as described
herein.
Definitions
[0023] Unless defined otherwise, all technical and scientific terms
used herein
have the same meaning as is commonly understood by one of ordinary skill in
the art to
which this disclosure belongs. In the event that there is a
plurality of definitions for a term herein, those in this section prevail
unless stated
otherwise.
[0024] In this specification and in the claims, the following terms
have the
meanings as defined. As used herein, "alkyl" means a branched, or straight
chain
chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-
propyl
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isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl,
neopentyl,
isopentyl and sec-pentyl. Alkyl groups can either be unsubstituted or
substituted with one
or more substituents, e.g., halide, alkoxy, acyloxy, amino, amido, cyano,
nitro, hydroxyl,
thio, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, heterocyclyl,
carbocycyl, or other
functionality that may be suitably blocked, if necessary for purposes of the
invention,
with a protecting group. Alkyl groups can be saturated or unsaturated (e.g.,
containing -
C=C- or -C-=-7C- subunits), at one or several positions. Typically, alkyl
groups will
comprise 1 to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and
most
preferably 1 to 2 carbon atoms.
[0025] As used
herein, "carbocyclyl" means a cyclic ring system containing
only carbon atoms in the ring system backbone, such as cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple
fused
rings. Carbocyclyls may have any degree of saturation provided that at least
one ring in
the ring system is not aromatic. Carbocyclyl groups can either be
unsubstituted or
substituted with one or more substituents, e.g., alkyl, halide, alkoxy,
acyloxy, amino,
amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl,
heteroaryl,
or other functionality that may be suitably blocked, if necessary for purposes
of the
invention, with a protecting group. Typically, carbocyclyl groups will
comprise 3 to 10
carbon atoms, preferably 3 to 6.
[0026] As used
herein, "lower alkyl" means a subset of alkyl, and thus is a
hydrocarbon substituent, which is linear, or branched. Preferred lower alkyls
are of 1 to
about 4 carbons, and may be branched or linear. Examples of lower alkyl
include butyl,
propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology
"lower"
refer to radicals preferably with 1 to about 4 carbons in the alkyl portion of
the radical.
[0027] As used
herein, "amido" means a H-CON- or alkyl-CON-,
carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group wherein
the
alkyl, carbocyclyl, heteroaryl, aryl or heterocyclyl group is as herein
described.
[0028] As used
herein, "aryl" means an aromatic radical having a single-ring
(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) with
only carbon
atoms present in the ring backbone. Aryl groups can either be unsubstituted or
substituted
with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl,
haloalkyl,
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alkoxy, nitro, halo, mercapto, and other substituents. A preferred carbocyclic
aryl is
phenyl.
[0029] As used
herein, the term "heteroaryl" means an aromatic radical
having one or more heteroatom(s) (e.g., N, 0, or S) in the ring backbone and
may include
a single ring (e.g., pyridine) or multiple condensed rings (e.g., quinoline).
Heteroaryl
groups can either be unsubstituted or substituted with one or more
substituents, e.g.,
amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto,
and other
substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl,
oxazolyl,
oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,
isoxazolyl,
thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,
thiazolyl
benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,
cinnolinyl,
indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl,
thienopyridinyl,
pyrido[2,3-cflpyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,
thieno [2,3-
c] pyridinyl, pyrazolo [3 ,4-b]pyridinyl, pyrazolo [3 ,4-c]pyridinyl, pyrazolo
[4,3 -c] pyridine,
pyrazolo[4,3-b]pyridinyl, tetrazolyl, and others.
[0030] In these
definitions it is clearly contemplated that substitution on the
aryl and heteroaryl rings is within the scope of certain embodiments. Where
substitution
occurs, the radical is called substituted aryl or substituted heteroaryl.
Preferably one to
three and more preferably one or two substituents occur on the aryl ring.
Though many
substituents will be useful, preferred substituents include those commonly
found in aryl
compounds, such as alkyl, carbocyclyl, hydroxy, alkoxy, cyano, halo,
haloalkyl,
mercapto and the like.
[0031] As used
herein, "amide" includes both RNR'CO- and RCONR'-. R
can be substitutented or unsubstituted alkyl, substitutented or unsubstituted
heterocyclyl,
substitutented or unsubstituted heteroaryl, substitutented or unsubstituted
aryl, or
substitutented or unsubstituted carbocyclyl. R' can be H or substitutented or
unsubstituted
alkyl.
[0032] As used
herein, "halo", "halide" or "halogen" is a chloro, bromo,
fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides.
Most
preferred halide is fluorine.

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[0033] As used
herein, "haloalkyl" means a hydrocarbon substituent, which is
a linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with
chloro, bromo,
fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one
or more of
the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are
of 1 to
about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons,
and most
preferred are 1 carbon in length. The skilled artisan will recognize then that
as used
herein, "haloalkylene" means a diradical variant of haloalkyl, such diradicals
may act as
spacers between radicals, other atoms, or between the parent ring and another
functional
group.
[0034] As used
herein, "heterocyclyl" means a cyclic ring system comprising
at least one heteroatom in the ring system backbone. Heterocyclyls may include
multiple
fused rings. Heterocyclyls may have any degree of saturation provided that at
least one
ring in the ring system is not aromatic. Heterocyclyls may be substituted or
unsubstituted
with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino,
amido, cyano,
nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, and
other
substituents, and are attached to other groups via any available valence,
preferably any
available carbon or nitrogen. More preferred heterocycles are of 5-7 members.
In six
membered monocyclic heterocycles, the heteroatom(s) are selected from one up
to three
of 0, N or S. and wherein when the heterocycle is five membered, preferably it
has one
or two heteroatoms selected from 0, N, or S. Examples of heterocyclyl include
azirinyl,
aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, 1,3 -
benzodioxolyl,
dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,
dihydrobenzodioxinyl,
dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,
dihydropyridinyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl,
thiomorpholinyl,
piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl,
oxazinyl,
thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,
isoxazolidinyl, piperidinyl,
pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.
[0035] As used
herein, "substituted amino" means an amino radical which is
substituted by one or two alkyl, carbocycyl, aryl, heteroaryl or heterocyclyl
groups,
wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined
as above.
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[0036] As used
herein, "substituted thiol" means RS- group wherein R is an
alkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl,
carbocyclyl, aryl,
heteroaryl or heterocyclyl are defined as above.
[0037] As used herein, "sulfonyl" means an a1kylS02, ary1S02,
heteroary1S02, carbocycly1S02, or heterocyclyl-S02 group wherein the alkyl,
carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.
[0038] As used
herein, "sulfonamido" means an alkyl-S(0)2N-, aryl-S(0)2N-,
heteroaryl-S(0)2N-, carbocyclyl-S(0)2N- or heterocyclyl-S(0)2N- group wherein
the
alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein
described.
[0039] As used
herein, when two groups are indicated to be "linked" or
"bonded" to form a "ring," it is to be understood that a bond is formed
between the two
groups and may involve replacement of a hydrogen atom on one or both groups
with the
bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring.
The skilled
artisan will recognize that such rings can and are readily formed by routine
chemical
reactions, and it is within the purview of the skilled artisan to both
envision such rings
and the methods of their formations. Preferred are rings having from 3-7
members, more
preferably 5 or 6 members. As used herein the term "ring" or "rings" when
formed by the
combination of two radicals refers to heterocyclic, carbocyclic, aryl, or
heteroaryl rings.
[0040] The skilled
artisan will recognize that some structures described herein
may be resonance foims or tautomers of compounds that may be fairly
represented by
other chemical structures, even when kinetically; the artisan recognizes that
such
structures are only a very small portion of a sample of such compound(s). Such
compounds are clearly contemplated within the scope of this invention, though
such
resonance forms or tautomers are not represented herein.
[0041] The compounds provided herein may encompass various
stereochemical forms. The compounds also encompasses diastereomers as well as
optical
isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as
individual
enantiomers and diastereomers, which arise as a consequence of structural
asymmetry in
certain compounds. Separation of the individual isomers or selective synthesis
of the
individual isomers is accomplished by application of various methods which are
well
known to practitioners in the art. Unless otherwise indicated, when a
disclosed
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compound is named or depicted by a structure without specifying the
stereochemistry and
has one or more chiral centers, it is understood to represent all possible
stereoisomers of
the compound.
[0042] The term
"administration" or "administering" refers to a method of
giving a dosage of a compound or pharmaceutical composition to a vertebrate or
invertebrate, including a mammal, a bird, a fish, or an amphibian, where the
method is,
e.g., orally, subcutaneously, intravenously, intranasally, topically,
transdermally,
intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally,
ontologically,
neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber
injection,
intravitreally, intraperitoneally, intrathecally, intracystically,
intrapleurally, via wound
irrigation, intrabuccally, intra-abdominally, intra-
articularly, intra-aurally,
intrabronchially, intracapsularly, intrameningeally, via inhalation, via
endotracheal or
endobronchial instillation, via direct instillation into pulmonary cavities,
intraspinally,
intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally,
intratympanically, intracistemally, intravascularly, intraventricularly,
intraosseously, via
irrigation of infected bone, or via application as part of any admixture with
a prosthetic
device. The preferred method of administration can vary depending on various
factors,
e.g., the components of the pharmaceutical composition, the site of the
disease, the
disease involved, and the severity of the disease.
[0043] A
"diagnostic" as used herein is a compound, method, system, or
device that assists in the identification and characterization of a health or
disease state.
The diagnostic can be used in standard assays as is known in the art.
[0044] The Willi
"mammal" is used in its usual biological sense. Thus, it
specifically includes humans, cattle, horses, dogs, and cats, but also
includes many other
species.
[0045] The teun
"pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" includes any and all solvents, co-solvents, complexing
agents,
dispersion media, coatings, antibacterial and antifungal agents, isotonic and
absorption
delaying agents and the like which are not biologically or otherwise
undesirable. The use
of such media and agents for pharmaceutically active substances is well known
in the art.
Except insofar as any conventional media or agent is incompatible with the
active
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ingredient, its use in the therapeutic compositions is contemplated.
Supplementary active
ingredients can also be incorporated into the compositions. In addition,
various adjuvants
such as are commonly used in the art may be included. These and other such
compounds
are described in the literature, e.g., in the Merck Index, Merck & Company,
Rahway, NJ.
Considerations for the inclusion of various components in pharmaceutical
compositions
are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The

Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.
[0046] The tem'
"pharmaceutically acceptable salt" refers to salts that retain
the biological effectiveness and properties of the compounds provided herein
and, which
are not biologically or otherwise undesirable. In many cases, the compounds
provided
herein are capable of forming acid and/or base salts by virtue of the presence
of amino
and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable
acid
addition salts can be formed with inorganic acids and organic acids. Inorganic
acids from
which salts can be derived include, for example, hydrochloric acid,
hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from
which salts
can be derived include, for example, acetic acid, propionic acid, glycolic
acid, pyruvic
acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically
acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic
bases from which salts can be derived include, for example, sodium, potassium,
lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the
like;
particularly preferred are the ammonium, potassium, sodium, calcium and
magnesium
salts. Organic bases from which salts can be derived include, for example,
primary,
secondary, and tertiary amines, substituted amines including naturally
occurring
substituted amines, cyclic amines, basic ion exchange resins, and the like,
specifically
such as isopropylaminc, trimethylamine, diethylamine, triethylamine,
tripropylamine, and
ethanolamine. Many such salts are known in the art, as described in WO
87/05297.
[0047] "Solvate"
refers to the compound formed by the interaction of a
solvent and a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitable
solvates are
pharmaceutically acceptable solvates including hydrates.
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[0048] "Patient"
as used herein, means a human or a non-human mammal,
e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human
primate or a
bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
[0049] By
"therapeutically effective amount" or "pharmaceutically effective
amount" of a compound as provided herein is one which is sufficient to achieve
the
desired effect and may vary according to the nature and severity of the
disease condition,
and the potency of the compound. "Therapeutically effective amount" is also
intended to
include one or more of the compounds of Formula (I) in combination with one or
more
other agents that are effective to inhibit Wnt related diseases and/or
conditions. The
combination of compounds is preferably a synergistic combination. Synergy, as
described, for example, by Chou, Cancer Research (2010), 70(2), 440-446,
occurs when
the effect of the compounds when administered in combination is greater than
the
additive effect of the compounds when administered alone as a single agent. In
general, a
synergistic effect is most clearly demonstrated at sub-optimal concentrations
of the
compounds. It will be appreciated that different concentrations may be
employed for
prophylaxis than for treatment of an active disease. This amount can further
depend upon
the patient's height, weight, sex, age and medical history.
[0050] A
therapeutic effect relieves, to some extent, one or more of the
symptoms of the disease, and includes curing a disease. "Curing" means that
the
symptoms of active disease are eliminated. However, certain long-term or
permanent
effects of the disease may exist even after a cure is obtained (such as
extensive tissue
damage).
[0051] "Treat,"
"treatment," or "treating," as used herein refers to
administering a compound or phattnaceutical composition as provided herein for
therapeutic purposes. The term "therapeutic treatment" refers to administering
treatment
to a patient already suffering from a disease thus causing a therapeutically
beneficial
effect, such as ameliorating existing symptoms, preventing additional
symptoms,
ameliorating or preventing the underlying metabolic causes of symptoms,
postponing or
preventing the further development of a disorder and/or reducing the severity
of
symptoms that will or are expected to develop.

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[0052] "Drug-eluting" and or controlled release as used herein refers to
any
and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption
by which
the drug(s) incorporated in the drug-eluting material pass therefrom over time
into the
surrounding body tissue.
[0053] "Drug-eluting material" and or controlled release material as
used
herein refers to any natural, synthetic or semi-synthetic material capable of
acquiring and
retaining a desired shape or configuration and into which one or more drugs
can be
incorporated and from which incorporated drug(s) are capable of eluting over
time.
[0054] "Elutable drug" as used herein refers to any drug or combination
of
drugs having the ability to pass over time from the drug-eluting material in
which it is
incorporated into the surrounding areas of the body.
Compounds
[0055] The compounds and compositions described herein can be used as
anti-proliferative agents, e.g., anti-cancer and anti-angiogenesis agents,
and/or as
inhibitors of the Wnt signaling pathway, e.g., for treating diseases or
disorders associated
with aberrant Wnt signaling. In addition, the compounds can be used as
inhibitors of one
or more kinases, kinase receptors, or kinase complexes. Such compounds and
compositions are also useful for controlling cellular proliferation,
differentiation, and/or
apoptosis.
[0056] Some embodiments of the present invention include compounds,
salts,
pharmaceutically acceptable salts or pro-drug thereof of Formula (I):
R2 / N
N \ NH
R1
\ N
[0057] In some embodiments, 121 is ¨heteroary1R3R4.
[0058] In some embodiments, R2 is selected from the group consisting of
H, ¨
heteroary1R5, -heterocycly1R6 and ¨ary1R7.
16

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[0059] In some embodiments, R3 is selected from the group consisting of
H, -
heterocycly1R8, ¨NHC(=0)R9, ¨NIISO2R10, -NR11R12 and -(C,6 a (C1_6
alkyl)NR11R12.
[0060] In some embodiments, there is the proviso that R2 and R3 are not
both
H.
[0061] In some embodiments, R4 is 1-3 substituents each selected from
the
group consisting of H, Cl..9 alkyl, halide, -CF3, -CN, OR13 and amino.
[0062] In some embodiments, each R5 is independently 1-4 substituents
each
selected from the group consisting of H, C1_9 alkyl, halide, -CF3, -CN, OR13, -
C(=0)R11,
amino and -(C1_6 alkyl)NR11R12.
[0063] In some embodiments, each R6 is independently 1-5 substituents
each
selected from the group consisting of H, Ci_9 alkyl, halide, -CF3, -CN, OR13
and amino.
[0064] In some embodiments, each R2 is independently 1-5 substituents
each
selected from the group consisting of H, C1_9 alkyl, halide, -CF3, -CN, OR13,
amino, ¨(C1_
6 alkyl)NHSO2Rt _NR12(c _6
alkyl)NR11R12 and -(C1_6 alkyl)NR11R12.
[0065] In some embodiments, R8 is 1-5 substituents each selected from
the
group consisting of H, C1_9 alkyl, halide, -CF3, -CN, OR13 and amino.
[0066] In some embodiments, R9 is selected from the group consisting of
C1-9
alkyl, ¨heteroary1R5, -heterocycly1R6, ¨ary1R7 and ¨CH2carbocyclyl.
[0067] In some embodiments, R1 is selected from the group consisting of
alkyl, ¨heteroary1R5, -heterocycly1R6, ¨arylle, and ¨carbocycly1R14.
[0068] In some embodiments, each R" is independently selected from C1-6
alkyl.
[0069] In some embodiments, each R12 is independently selected from the
group consisting of H and C,6 alkyl.
[0070] In some embodiments, each R" and R12 are optionally linked to
form a
five or six membered heterocyclyl ring.
[0071] In some embodiments, each R13 is independently selected from the
group consisting of H and C1.6 alkyl.
[0072] In some embodiments, R14 is 1-5 substituents each selected from
the
group consisting of H, C1.9 alkyl, halide, -CF3, -CN, OR13 and amino.
17

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[0073] In some embodiments, there is the proviso that Formula I is not a
structure selected from the group consisting of:
/ \
\ / N
N--
N-- \
0NH \ \
0
./ N\ NH N \ NH
I I I ti N., NI., N-õ,
\N \
\iN )s4 / NIN
N N N
H / , H H H
õõ
7
'
0NH 00001...v4 NH
N,
N \ NH \ ____Z,NH ../ \ NH /N /N
\ NH
I I I
,,, I N ,--*
/ /
N N NiN
H H H
, H , ) ,
N N,,,,,õ
- , / ,
\
NH N, \ ['-- ''NH NH 0 NH
N \ NH / N \ NH \ N \ NH
1 I 1
\ \ N N N NI N'
H H H H
N
N ----?
NH raicHCH
rk. \ NH NH
I I
\,
N
H H H , NK1
, , and
\ / N
NH \
N-JN N\ NH
I
\
\iN
N
H.
[0074] In some embodiments, R1 is pyridineR3R4.
[0075] In some embodiments, R1 is pyridin-3-y1R3R4.
[0076] In some embodiments, R3 is H.
[0077] In some embodiments, R3 is -(C1_6 alkyl)NR11R12.
[0078] In some embodiments, R3 is -(C1_4 alkyl)NR11R12.
[0079] In some embodiments, R3 is -(C1_2 alkyl)NR11R12.
[0080] In some embodiments, R3 is ¨C112NR11R12.
[0081] In some embodiments, R3 is ¨NR11R12.
18

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[0082] In some embodiments, Ril is -(C1_2 alkyl).
[0083] In some embodiments, R12 is -(C1,2 alkyl).
[0084] In some embodiments, R12 is H.
[0085] In some embodiments, R4 is H.
[0086] In some embodiments, R4 is amino.
[0087] In some embodiments, R11 and R12 are linked to form a five or six
membered heterocyclyl ring.
[0088] In some embodiments, R11 and R12 are linked to form a morpholine
ring.
[0089] In some embodiments, R" and R12 are linked to form a piperidine
ring.
[0090] In some embodiments, R" and R12 are linked to form a pyrrolidine
ring.
[0091] In some embodiments, R" and R12 are linked to form a piperazine
ring.
FF
[0092] In some embodiments, R11 and R12 are linked to faun CJIV .
[0093] In some embodiments, R3 is ¨NHC(=0)R9.
[0094] In some embodiments, R9 is -(C2.5 alkyl).
[0095] In some embodiments, R9 is phenyl.
[0096] In some embodiments, R9 is ¨CH2carbocyc1yl.
[0097] In some embodiments, R3 is ¨NHSO2R1 .
[0098] In some embodiments, R1 is ¨(C1_4 alkyl).
[0099] In some embodiments, R1 is phenyl.
[00100] In some embodiments, R3 is ¨heteroeycly1R8.
[00101] In some embodiments, R3 is morpholine.
[00102] In some embodiments, R3 is piperazine.
[00103] In some embodiments, R3 is piperidine
[00104] In some embodiments, R3 is 1-methylpiperazine.
[00105] In some embodiments, R2 is ¨heteroary1R5.
[00106] In some embodiments, R2 is -pyridiny1R5.
[00107] In some embodiments, R2 is -pyridin-2-y1R5.
19

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[00108] In some embodiments, R2 is -pyridin-3-y1R5.
[00109] In some embodiments, R2 is -pyridin-4-y1R5.
[00110] In some embodiments, R5 is 1-2 fluorine atoms.
[00111] In some embodiments, R2 is thiopheneR5.
[00112] In some embodiments, R2 is furanR5.
[00113] In some embodiments, R2 is imidazoleRs.
[00114] In some embodiments, R2 is selected from the group consisting of:
__ )--\ 0 \ s s s
0
N F and
N N
, .
[00115] In some embodiments, R2 is ¨heterocyc1y1R6.
[00116] In some embodiments, R2 is morpholine.
[00117] In some embodiments, R2 is piperazine.
[00118] In some embodiments, R2 is piperidine
[00119] In some embodiments, R2 is 1-methylpiperazine.
[00120] In some embodiments, R6 is selected from the group consisting of H, F
and ¨(C1.4 alkyl).
[00121] In some embodiments, R2 is ¨ary1R7.
[00122] In some embodiments, R2 is ¨pheny1R7.
[00123] In some embodiments, R7 is 1-2 fluorine atoms.
[00124] In some embodiments, R7 is ¨(C1_6 alkyONHSO2R11.
[00125] In some embodiments, R7 is ¨(C14 alkyl)NHSO2R11.
[00126] In some embodiments, R7 is ¨(C1_2 alkyl)NHSO2R11.
[00127] In some embodiments, R7 is ¨CH2NHSO2R11.
[00128] In some embodiments, R7 is ¨CH2NHSO2CH3.
[00129] In some embodiments, R7 is -NR12(C1.6 alkyl)NR11R12.
[00130] In some embodiments, R7 is _NR12(--.1.4
alkyl)NR11R12.
[00131] In some embodiments, R7 is -NR12CH2CH2NR11R12.
[00132] In some embodiments, R7 is -NHCH2CH2NR11R12.
[00133] In some embodiments, R7 is -NHCH2CH2N(CH3)2.

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[00134] In some embodiments. R7 is 2 substituents consisting of 1 fluorine
atom and -NR12(C1-6 alkyl)NR11R12.
[00135] In some embodiments, R7 is 2 substituents consisting of 1 fluorine
atom and -NHCH2CH2NR11R12.
[00136] In some embodiments, R7 is 2 substituents consisting of 1 fluorine
atom and ¨(C1-6 alkyl)NHSO2R11.
[00137] In some embodiments, R7 is 2 substituents consisting of 1 fluorine
atom and ¨CH2NHSO2R11.
[00138] In some embodiments, R1 is pyridin-3-y1R3R4; R3 is H; R4 is H; R2 is
selected from the group consisting of pyridine and ¨heterocyc1y1R6; and R6 is
selected
from the group consisting of IT, F and ¨(C1,4 alkyl).
[00139] In some embodiments, R1 is pyridin-3-y1R3R4; R3 is H; R4 is amino; R2
is selected from the group consisting of ¨heteroary1R5, ¨pheny1R7 and
¨heterocyc1y1R6;
R5 is H; R6 is selected from the group consisting of H, F and ¨(C1_4 alkyl);
R7 is 1-2
fluorine atoms; and the heteroaryl is selected from the group consisting of
pyridine, furan
and thiophene.
[00140] In some embodiments, R1 is pyridin-3-y1R3R4; R3 is ¨NHC(=0)R9; R4
is H; R9 is selected from the group consisting of ethyl, propyl, isopropyl,
butyl, isobutyl,
tert-butyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
phenyl; R2 is
selected from the group consisting of H, ¨heteroary1R5, ¨pheny1R7 and
¨heterocycly1R6;
R5 is H or F; R6 is selected from the group consisting of H, F and ¨(C1_4
alkyl); R7 is
selected from the group consisting of 1-2 fluorine atoms and ¨CELNHSO2R11; and
the
heteroaryl is selected from the group consisting of pyridine, furan and
thiophene.
[00141] In some embodiments, R1 is pyridin-3-y1R3R4; R3 is ¨CH2NR11R12; R4
is H; R2 is selected from the group consisting of H, ¨heteroary1R5, ¨pheny1R7
and ¨
heterocycly1R6; R5 is selected from the group consisting of H, F, Me and ¨C(---
0)Me; R6
is selected from the group consisting of H, F and ¨(C14 alkyl); R7 is 1-2
fluorine atoms;
R11 and R12 are linked to form a five-membered heterocyclyl ring; the
heterocyclyl ring is
substituted with 1-2 fluorine atoms; and the heteroaryl is selected from the
group
consisting of pyridine, furan and thiophene.
[00142] Illustrative compounds of Formula (I) are shown in Table 1.
21

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Table 1.
--17----\
'-------- --N/Th
-N
ONH 0 NH
N \ NH
\ N
I '' N\ NH 3
NH 2
1
NI N ,-, N
\ N \ N \ N
/ N/
N Isl
H H H
0/Th
/ NV__,..yrsi / 11
4 -,,, N\ NH 5 ,,, N\ NH 6 ,----õ, N\ NH
NI N I
\ \ N N
N/N
NI
H H H
NI
F
'''---...---
---- ---. / N
0NH
/ N\ NH
7 \
\ N ----,
8 0.,-,,NH \ N\ NH 9 r'
N ------
NI 11 N H
H
H
F
F
F
.--",
.---.
\ \ /
õ,...---,...õ 0,---.. NH \
0NH
0.NH --__ -----
N\ NH 11
\ NH 12 N\ NH
-.,
N
\ N
\ N 1 N
N/ H H
H
F F F
F
F
..õ..---.,,
\ \ \
0'.-
NH
13 LtH 14 N \ NH 15 N\ NH
-..,,
\ N \ N \ N
Isi N/ Ni
H H H
22

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PCT/1JS2013/031055
F
F
N
\
O 0
\ / N
Ok_sõ...,0s....e. --....õ \
*
..' N
---.._ 10 ' N H --..._
N \ NH
16 17 N\ NH
N18 õ
--., \ NH "---1
\
N
\
\ N N N/
Ni H
N/ H
H
F F F
F
/ N
0....,õe0
0NH
NH --....__ ONH .-...õ,
19 N \ NH 20 N\ NH 21 --.., N\ NH
-..,..
i
i N ,..--
N .õ---' \N
N N'
L"----,-----------N/ N H
H H
F
F F
"õ------...,
/ N
= \
O'
0N H \ \
0 N H
--...__ ''''NH F
F -......._
22 --., NNH 23 -....., N
\ N H 24
-., N \ N H
i I
N õ..., N ,---' N õ..--"
\ N "N "N
N/ NI
i
H H N
H
= \
0N H \
--......_
25 N \ N H 26 1
N 27 N \ N H
-..,
I I I
Nõ..----
\N "N \N
Ni N/ N
H H H
F F F
\
= \ \ ONH -
.....__
0 --
NH 0 N H
---..
N \ NH
28 .. N \ N H 29 N \ NH 30
,.., ...,,
I
I I N N ,---
,..,' \ N
\ N \ N N/
NI
N/ H
H
H
23

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PCT/1JS2013/031055
F F
F
\ 1 1
0NH 0N H -, 0NH --.,_
31 , N \ NH
,,, 32 ,õ N\ NH 33
I
, -.. N\ NH
NI / N ,,,
N ,,
\ \ N \
/N / N
N N N/
H H H
F F A) F
0,'-,NH
0.,"--NH --õ,
0 NH ..,,,,
N\ NH
34 ,.., N\ NH 35 N\ NH 36
I
\ N \ N \
iN
N/ N
Ni
H H H
-,
-...õ,..e.õ....- F ,.. F
0 F
N=-=NH 0.,NH 0..."--..
NH-------
37 ..., N \ NH 38 -., N\ NH 39 N/Y\
N
\
/IN N
N Ni NI
H H H
F
F AI F
/ N / N / N
0NH 1 1 ON \
-..__ 0 NH
40 ,.., N \ NH 41 N \ NH 42
I N ./ N
N / \ N
\ N \ N
N
N/ H NI
H H
F F F
ON
/ N .--.) / N HOõ.,,
/ N
\ -..,,.M11 1 N 1
,
43 N \ NH 44 45
-, NH
\ N \N \ N
Ni
/
Ni N H
H H
24

CA 02853703 2014-04-25
WO 2013/151708 PCT/1JS2013/031055
_
F F F
N-----, N
46 N\ NH 47 N \ NH 48 N \ NH
-,
H
I N N /
/ N ./
\N \ N \ N
N/ N/ NI
H H H
F OH F
HC
/ l'\1
\____/N
N
\ N \
.--_ N \ NH
49 N \ , NH 50 N \ NH 51 -,
.., ,,,
NI ,'
NI ,= NI ,7 \ N
\ m \ N
N1'
N/ Ni
H
H H
HN/--- 11147- ,"-1 HNON z N
"-----N / \
N\ NH
52 N\ NH 54
IV il
N ..-- N
\ N \ \ N
iN 14/
isi N
H H
H
HO HO
HO ,..õ---) HCNI
N / Il \ ON \
--__
--.,N ------,
N\ NH
55 1 -- N\ NH 56
NI \ NI _. \
\N N N
N' N/
NI
H
H H
HO HO
HO
/ N / N HO,N.õ---..,1
/ N
----
58 ,,,, N \ NH 59 N \ NH 60
I \ NH
\N
\ N
N/
N/ H
H H
HO HO HO
0 / N
'NH NH \ \ 1
--)11,1H
-, -, -..õ
61 ,, N\ NH 62 ,õ N \ NH 63 1 N
\ NH
NI ,,,, N ,-
NI ,, \
\N \ N
N
N/ Ni N
H H
H

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HN/Th HN/--- n Hisr-)
0 / M1\1 0 7 ,,)L,
NH NH '.'1'NH
64 ,,, N \ NH -,
65 N \ NH 66 r N \ NH:
NI õ7 N
\N \N \N
NI Ni
N H H
H
\ \ \
/N N
/N
/ ---\
0
0 / N / N / N
\ \ ,-"...L--.
--)Y\
67 NH F 68 NHF
N\ )69 NH F
N\ NH NH \ NH
1 '.
1 N
\N
14\N \ N N/
/ N/ H
H H
ON
N
, / N
\ \
--jINH F U "H F HN F
70 -.._ 71 72 i
N \ NH N \ NH
N \ N
N
N H
N N/ iiN
H H
O / N 0 / N / N
\ \)1 r 1 75 1
73 '---)L-NH F NH = --.._ -)NH F -,
N \ NH N \ NH N\ NH
-.
1 1 NI
N N / \N
\ N \ N 1,1(
NI Ni H
H H
ON CN ON
O 0 0
/ N / N / N
' 76 NH \ /1L, F \ \ \
= ----- 77 -,1-NH F 78
N\ NH N
,. \ NH
I
1
N /
\ \ N
/N N/
IV
N H
H H
26

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HO HO
HO
-0 --CN --ON
/ \
\
....-Ii--NH F 1
79 NH . ----. \ 80 NH F --__ 81 ..,_
N\ NH N \ NH N \ NH
FrL''
\ N
N
N/ NI/ H
H H
F F F
82 N/ --1'-- 83 N \ NH
N ,,,/ 84 N \ NH
\ NH -,
I I
N ,-, \
\ N \ N N
71
1\1/ N/ NH
H H H
F F F
\ 1 1
0'--- NH 0 NH 0 NH -__
85 N\ NH 86 ,, N \ NH 87 ., N \
NH
NI \ NI N _.,
/
\ \ N
N /IV
Ni N N
H H
H
F F F
X
/ N
\ \
NH -, \ ---- ---. -____ -.._õ
88
0-.NH N \ NH 89 N I 90 N \ NH
/N
N ," N
H H H
F F F
OYNH / N
0
\ IN H / N
\
0 NH
--__
91 N \ NH 92 N \ NH 93 N \ N H
-., ,,
NI
\ N \ N \ N
N/
H H H
27

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0 F F F
*
C / N
1 HN 1 HN 1
0;NH N 94 95 N\ NH 96 N\ NH
),NH .=
1 IN1 __.õ.
IV \N _,---
N ,/ \.
\N
N)' 14/
Ni H H
H
F F F
1 1 \
N \ NH N \ NH N \ NH
98 =,. 99
1
N / I
ri /
\N \ \N
/IN N
N/ NI
N
H H H
F/F
/ Nk /
HN
0NH \
--,
N \ NH 102 N \ NH
N \
100 N\ NH 101 rH .,.
NI
N N
NI
H H - H
F
\ \
0 NH 0 NH
103 N\ NH 104 N \ NH 105 ,.
1 -...
NI
N NI \ N
\ \
iN /1\1 Ni
N N H
H H
F F
F
/ N
1 1
..
N \ NH
106 107 108 ,
N ../ \N NI
N .,
\N \N
N/ Ni isli
H H
H
F
0NH 1
0NH ----- \ 2 F
0 NH \
----
109 N\ NH 110 '''' I N\ NH 111
NI ,,
\N \ N \N Ni Ni
N/ H H
H
1
28

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F
0NH \ \ HN I
112 .., N\ NH 113 ,, N\ NH 114 .,õ N\ NH
NI II NH.,
\
\ N \N /N
NI/ Ni N
H
H H
F F
C-1 F
\ NIH
115 , -,. N \ NH 116 ,õ N \ NH 117
N ./
\ \ N \N
N/
N
H H H
F F F
--___
118 .., N J.
\ NH 119
ir'''i \ NH 120
NI ,. N ,-,
N
\ N \ N "N
14/ N/ N/
H H H
F F F
I
\
0NH
0NH \ \
-..._ 0 NH
121 N\ Ni_i 122 N \ NH 123
riTh
NI I
N
\N \N \N
N/
NI Is1/
H H H
F
F F
1 \ C\N \
NH .-- ---. --._ =¨____
,
124 ,, N \ NH 125
N \ NH 126
NI I
\ N ( 1 N \N
Ni
H H H
F F F
\ X
/ N
\
0XNH / N
\
---, ¨____
127 ., N \ NH 128
N \ NH 129
N \ NH
I
\N \ N \ N
Ni Ni N/
H H H
,
29 '

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
(DINH F
/ N
\ T F
/ N\i
9 F
/ N
,. 0 NH
130 -., N\ NH 131 ., \ NIH 132
ll N NI
\ N \ N \N
N
N/ I,
NI
H H H
0 HI F
C1-1 F
\ / N
\
/ N \
HN--, NH2 -.._.
133 N 1 134 /,---, N \ NH 135 NH
\
,NI
------- -N/ N
N H H H
N N
N / \
/ \
,õ --r---?\
\ NH 137 -.., N ----- \
\ NH 138
136 N \ \N HN
N ----- \
\ NH
I
N / NI .,
/ N \ N
Ni N Isi
H H H
N N N
/ \
\ / N
1 / N
\ \ \
."NH --- '--.. =¨_,
139 N \ NH 140
I N\ NH 141 N \ NH
N / N =,,,, \
N N
N
N/ \-----'----1 Ni
L\%------1 NI
H H H
N N N
/ \
ON \ -------N---, \
0INH \
N\ NH
142 ,, N\ NH 143 r' N\ NH 144 .,.,
NI
\N 11'N
Ni
H H H
IN
, ,
, , N T
\ \ \
0 NH ¨..õ, 0 NH -__ 0 NH
145 N\ 141.1 146 ,, N \ NH 147
1 I 1
N
\ N \ \ N
71
NI N NI/
H H H
,

CA 02853703 2014-04-25
WO 2013/151708
PCT/US2013/031055
CI) N
/
/ N
/N \
1 / N
(:)NH
HN \ HN \ --__
N \ NH
N \ NH 150
148 N \ NH 149 -,,
,,
I
\ N \ N
\ N
14/ N
Ft H H
'
N/ \ /
N/ \ N \
õ....---.õ,
\ NH2
ONH -____.
151 I
\ 152 153
NH N \ NH
N
I I
N
N /
N /
N / \ \
\ M1//N N /M11
M11/ H
H H
/
N \
/
/ N ''l N/ \ N N/ \
/ N
\ HN-.
--...,_
--__
N\ NH N,
154155 r'' N \ NH 156 -., \ NH
II I
\ N \
N N
Isc -N..-------Ni 14/
1-1 H H
M11"--1 / N N/ \
N/ \ / N
0".NH \
0NH \ / N
-..._ \ -____
I 0 NH ,
157 'N\ NH 158
I '' N \ NH 159
I N \ NH
N /
\ m N /
'I N
Nj. \ N
M11/ Ni
H H
H
N/ N N / \
\ 1
I / N
/
/
\ N \
0 NH
.-'--NH
--___ N \ NH
160 N) NH 161 ,, N\ NH 162
..,
NI _.
\ N \ N
\ N 14/
Nj
Isli H I-1
H
,
N/ \
N"\
X. N/ \
/ N
0-INI-1
/N
N
N --....._
163 164
M11 165 -,, N \ NH
I I
/ N / /
\ \ N \ N
tsi N'H H H
31

CA 02853703 2014-04-25 =
WO 2013/151708 PCT/US2013/031055
/
N \
/ N -õ /
N \
/ N
\
\ \ 0 NH
0 NH 0NH --__.
N 166 -,, N\ NH 167 N \ NH
\ NH 168 (L
N- \ N
\
Iki l,
Isc H
H H
1 N/
/ N
\ \ \
0 NH NH --____ 0 NH
169 170 N, N \ NH 171
N / I
NI /
\ N \ N N õ'
\
N/ /N
NI/ N
H H H
/
N \
/ N a
HN N/ \
/ N ..,,
0
NH / N
\ / N
\
/y HN 1 -...õ
172 N\ NH 173 174 ,.,
NI 7-
I I
\ N \
N Isi
Ni Ni H
H H
,
/ N \ 1
_õ---,
\ /
\ \
,
\ eNH NH2
N \ NH N \ NH
177
175 I,.,. N\ NH 176
N5\
N .7. N \ N
N 14/
N/
H H H
/ N / N / N
\ / N '1 \ /
\
\ HN -..._
\
.-___ -----
N\ NH N \ NH
178179 Nõ N\ NH 180 N.,
11 IV I
N / N
\ N \ N \ N
NI Ni Ni
H H H
/
0 0 NH
.,NH , \
-_____ --..._
0 NH ,
181 182 N\ NH 183
(L N I
\ NH
!
N
\ N \ N
Ni
H H H
32

CA 02853703 2014-04-25
WO 2013/151708
PCT/US2013/031055
n / N / N
\ 1
1 'NH
0'=-=,NH N \ NH
184 N\ NH 185 .., N \ NH 186
NI ,/
\ N
N H H
H
N
>\
0 NH
187 188 NH 189 :,õ () \ NH
NI
N 7,/
\p \ \ N N
Nj Ni
N
H H H
--, .-,
1
0XNH--____ -....,_ =-_,
0'NH 0=,-.NH N \ NH
190 ,,. \ NH 191 d ,,,, N \ NH
IV 192
I -.'
v- I / N
\ N
\ N \ N N/
N' 14/ H
H H
\ \ \
0 NH NH NH
193 ,, N\I/J NH 194 N I
\ NH 195
NI I
N ,.
\ N \ N \
N
/
N/ N N
H H H
CN
/ N kill / N
\ /
N
\ '1
ONH ON
/ N
1
HN 1 HN ,
, N \ NH
I
196 197 ., N \ NH 198
NI N
\
iN N/
N H H
H
\
0. , . NH NH2
N\ NH
199 N \ NH 200 ,..,. . Nc INH 201
I NI
N N/
N
H H
H
33

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
HN ON / N
ON / N\
,, I-1
\ NH 203 ,..., N \ NH 204
202
II
,-. NI
N ,,
\ "N \N
/N
N
N/
N N/
H H H
O
ON / N 0NH 0 NH
ON / N
1 1
0."-
NH 1
205 -,, N\ NH 206 .., N\ NH 207 N\
N N I \ NH
\ N \N N .,
\N
N
Iti
Ni
H H H
ON / N
NI CN / N
NH
1 -7 /
0 NH N\ NH
208
N N\ NH 209 N \ NH 210
II
NI =-= \ N
\ N
\N 1,.."1õ, ,N
N/
isi rF1 H
H
..'''. X
ON N / N
ON / N
1 1
0 NH
211 N \ NH 212
I '''. N\ NH 213
ri N \ NH
N
\ N \
N N I ' N
\,---.'' Ni
H H H
,
l'
ON / N
1 1 0 NH CN
0 NH ,-,
0 NH N\ NH
214 -., N \ NH 215 ,õ N\ NH 216 ..,
N/ / \ N
\ N \
N/ N N
N/ H
H H
ON / N T ON / N 9 ON / N
0NH 0 NH 0 NH
,
-., N I
\ NH 218 ., N \ NH 219 1
, - .
217
N NI
Is
\ N \N \N
N/
N/ N
H H H
,
34

CA 02853703 2014-04-25
WO 2013/151708
PCT/1JS2013/031055
0
3 / N \ 0 / N
HN
1 0NH
HN \
N \ NH
220 N\ NH 221 N 222
\ NH
[ r NI
\ N N
N/
H H H
,-7\ ) \
N N / N,
N N / N
1 N N / N
0'=-= NH -__ NH2
223 224 ,,, N \ NH 225
/*I NI ,--
\ N \ N \N
/
Ni
N/ N
H H H
)----\
) \
N N /
.,./, N N N / N
\
N N / N
=,_, 1 HN \ --...N----
---__
226 .., N \ NH 227 228 ,,,, N
\ NH
NI
N
N /
\ \ N \ N
iN
N/
N/
N
H H H
-
) \
N N / N
,
\ N N / N
\ N / N
\
0NH e-'1µ1H --___ 0 NH --_,
229 ,, N\ NH 230 ,,, N\ NH 231
N .,, NI \ NH
\ 1)' N \ N N ,...-.
.....õ \
N/ 14/
H H H
)___ \ )_... \
N N / N
NI )_____\
N N / N,
=NN.,
N,zN / N ..7 \ \
\ NH --....._ / -....,,
0 NH ,
N \ NH
232 N \ NH 233 N\ NH 234 .õ
(L
I
N \
\ N N /IN
N/ N
H H
H
--\
N N / N
..,,
N N / N
ON \ ==,,,,,N --__ 0 NH
235 236 237
N .'.Ni NI
\ N N \ N \ N
Ni
14/ Ni
H H H

CA 02853703 2014-04-25
WO 2013/151708
PCT/1JS2013/031055
N N / N N N / N, ,
0y NH
0 NH ---,,, 0 NH --__
238 ,,,, N \ NH 239 ,õ N \ NH 240
(LN \ NH
N NI H
H H
N _
, \ ,
0 NH 0 NH / 0 NH
241 ,, N \ NH 242
N \ NH 243 N \ NH
I
NI 7 N _. N õ..."-
\ N \ N \ N
IV/ Ni N
H H H
-\
HNI 1µ1,rN / N N N / N
=,õ- HN 0NH
\ 1
,
244 245 , --. N\ NH 246
I
\ NH
NI
\ N \ N
\ N7" ,,,
Ni IN/
H H
H
---/Th / ----17---A
N
HN \
N-,
NH2
247 .., N\ NH 248 (---- N\ NH 249 r' N
\ NH
NI
\N \ N \ N
NI
NI NI/
H H H
0--.NH
'
0 NH
250 N\ NH 251 N \ NH 252 N\ NH , \
I I
N /
\ N \N \ N
N/
H H H
----1-----\ .IN(Th
N / N\I
0 NH N \ NH
253 N \ NH 254 ,., \ NH 255
il
NI 7
NI 7 N 7
\ \N
\ N NIN N
N/ H H
H
,
36

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
X
0NH 0,'N
NH
256 ..,, N\ NH 257 ,., N\ NH 258 N \ NH
NI 1 NI /
\ N N ,.,
\ N \
/N
/
N N/ N
H H H
---/----) y -0 / N I ---N/P---\
O \
0 NH
0,-. NH I NH
259 N\ NH 260 .., N\ NH 261 N\ NH
..,
N _., N
\ N \ N
\ N N N
Ni H H
H
? --N/--- ? ---Kr- 0 ----N/Th
/
HN
0 NH 0 NH
[
262 N
N 1
\ NH 263 õvL.1 N \ NH 264
./ \N
H H
-..
/ N
/ t,\I
0..-N NH
0==NNH \
-__
-...___
265 ., N \ NH 266 1411 267 ..,
IV
N\ N \ NH
NI N
\ \ N
N/ N ti
H H
H
NH
/ N
\
p
NH2 ---,_
N \ NH N\ NH N \ NH
-,
268
N15 269 I 270 I
N N /
\ N II
\ N \ N
N/ / 14/
N
H H H
/ N
\
pl
HN \ N.N.--
-N. -.._
0N--NH
-.....,
N \ NH N \ NH
271 N\ NH 272 273
N
\ N \ N
11/14
NI IV
H
H H
37

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
/ N
\
/ N NH ---,,
\ \ N \ NH 0 NH ¨_, 0 NH
274 N 275 N \ NH 276 I
\ NH , N /
lki \ N
Ni /
\ \ N N/
iscN
N/ H
H H
NI ,---N
01 p
õN
.,-,
\ NH -,,
277
\ NH 278 ..,
\ NH 279 ,.
I
N ,7 NI
N
\ \ N \ N
1\1
N/ Ni
N/
H H H
X
\
0NH \
0NH \
0 NH --___ --__
280 N\ NH 281 .., N \ NH 282 N\ NH
1
N
N / \ N
N ! , N
N/
' ---Ni
H H H
0XNH 0 NH --___ / N
\
I , rsi
0NH
, 0
/ N
\
---,.
283 N\ NH 284 -õ N \ NH 285
I NN _.=
\ N /
\ N \ N
71
N N/
N H H
H
9 , N
\ HN-. (1 CI)
\
286 N\ NH 287 Nr/ 288
\ NH
N /
\
N/ H
H
H
i¨
S
0NH
--_,
0-,NH ,
N\ NH
N \ NH 291 (L
289 IN\ NH 290 -,
ij \ ,..- N õv
N N/
H H
H
'
38

CA 02853703 2014-04-25
WO 2013/151708
PCT/US2013/031055
S /N
I I HN,õ \
--_,
--__
--__
,
N N \ NH N
292 (' \ NH 293
294
11 \ NH
N ,/
N \ \N
N
\%-t---N1
Ni
H H H
7 \/ /¨
S
\
"=,,N...--- \
0 NH
0
NH
--__ -__
\ -,-., \
' 295 --...,
NI .,....õ N NH 296 N \ NH 297 N NH
I
N ,---
I IN \ N
Nj
Ni .""-----"-- ---N H
H H
/
\
NH---......,
\
0 NH --....... 0 NH --__ N \ NH
298 N \ NH 299 N \ NH 300 -.,,,
, --, -....,
NI ..7
I I \ N \ . \ N 7 NI
T'
N N/ H
H H
i_
/
----------1 i
S 7 / N s .7 /
N
N \ 0 \ --,,,,,,,,K,õ \
--__
N
N .
301 \ NH 302
303
N..õ---
\N N
N',,1_14/
H
H H
>Ns /¨ ---õ, 7¨ =--õ,
S 7 / N s7 /
\
0. NH \ 0 NH \
0 NH --_, --__
304 N\ NH 305 --,, N \ NH 306
(L I I
N ,-' N
\ N \N \ N
LL N N N/
H H H
/¨ /¨
\ \ \
OXNH --.... 0 NH 0 NH
N N \ N H
307 ...õ, NJ
\H 308 ,., \ NH 309 -...,
I I 1
N
\N \N
N/ Isi Ni
H H H
39

CA 02853703 2014-04-25
WO 2013/151708
PCT/US2013/031055
0 /¨ \
CI) /
S , / N ---..õ
0 NH
\
S
FIN, \ HN
---, ---- N \ NH
310 N \ NH 311 , - - = -... N \ NH 312 ...,
(-- N ,..õ., \ ..õ. N
N z \ \ N
,;1 N/N Ni 111/
H
H H
/
o7 / N 0 7 / N
\ \
\ NH2 ----,
0'----.NH -___
N \ NH
313 - . , N \ NH 314 i I -,, N\ NH 315
I - -., .,
1 N
N 7 \ \
14 N N
N/ H H
H
/ ¨
0 7 /N
\
I H N \ "----. ---'
,
N
N\ NH 318
316
N \
317
NI '',..õ... 1
_.--- N 7-
N \ N \
N
/
N N
Is
i i
H H H
\ `'=:_71C,, /¨
)...y
0.,,.
NH
\
0NH -....,_
0NH--..,...
--., N\ NH .... , H 321
NI ____... N\ N N \ NH
319 320
i (L'
N z' \ N
\ N z' ,,,, \
/
N
NN /H N
H H
/¨ /¨
I N \
NH ---- ---õ,_
\ --..,
3 N 323 H N\ NH 324 -....,
I
22
-..,,,, \ NH
I N 7'
\ 7
\
N 7 N
\ N /N N /
N N
N" H H
H
/¨
------'-'1 /¨
X
ON \ .=,õ,, N \ 0 7 / N
\
----, --____
--__.
0 NH --....._
325 r' N \ NH 326
I - - ..,,. N\ NH 327 ,,,
N \ NH
I
\ N \ N N 7
\ N
N/ Ni Ni
H H
H

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
..,
0 7 / N ,
\ \
Ce---NH 0 0XNH,...,%"..NH --__
N\ NH
329 N 330
328
\ NH , .....,
\ N \
14/ N H
H H
_
/¨
I
\
N \
0 NH 0 NH 0 NH
331 -.., N \ NH 332 -...., N \ NH 333
I 1
ts1 õ...._
\ \ \
N N /N
NI Ni N
H H H
F
0
i_
HN
N N
\ \
H \
--_,
334 \ NH 335 N \ NH 336 N \ NH
ii 1 1
N
\N
\ N \
N/ Nj JN
H H N
H
FF..., F...,
F / \
' / N
/
¨......,_
N\ NH 338 \ NH
I 1 1
"N \
11 N
/NI
N N
H H H
F F FVõ, FV...,
/
ni \
/ N /N
\ / N ON / N
-....._
N \ NH
340 341 N 342 ,...õ
I I I
,-- N .......--
\ N \N \ N
NI N/ isl/
H H H
FV...,
.N7Th F....
gi
344 ..., N\ NH 345 ,..., N\ NH
1 1 I
\ N \ N \ N
/
N.'
11/ N
H H H
41

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
\
/_____-,
FV., F /
..... 0
S \ \ HN
c,,,,N \ c.,)=1. \ -...,
---- / 347 Is\I
I N \ NH
N \ NH
346 348 ONH F
I N -----
-...., \ NH
I
N -/ iki
H H
H
\ \
HN/----/ HN HN
õ..-----,
\ 351 F' --__
349 -,-- F
0 NH
2'i) 350 H2N
N \ NH --,.., N
\ NH
--, -...,
V-NH
I
I
\ \ N N/14
iN
N Nt
H H H
N--...,
7----/
HN' HN
HN
\
F , \ 353 HN
F , \ 354
352 '-F
N
N \ NH
\ NH
--...õ il
N õ,...,
N ,---
N\ \ N \ N
Ni
N/
H H H
\ \ \
/-----/ /-----./ /----./
HN HN HN
-"-.....-""
',../
\ 357 0 NH F
355 C 0 NH
e."NH F ---- \ 356 F
,
N \ NH N \ NH
--.,
,..,,,
NI .7.
N õ.õ,..
\ \N \ N
/ N/
N
NI
N H
H H
\ \
N---__ õ,-----/ /-----../
/---,/
? HN HN HN
l'\I
NI / t,\I
358 0 NHF , \ 359 ---"NH F 360 --- F
,
N\ NH N \ NH .....,õ N
\ NH
,.., =-=.õ
I
I
NI
N ,--- \ N I N/
Ni ----- N/ H H H
42

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
\ \N___
\
HN' HN z--.....
HN
.._,.. \ ON \ \
363 _
361 0 -, F 362 F -......_
N \ NH \ N \ NH N \ NH
-,...,,
1 >10 i NH, F
N .,..,
\ N \ N
\
,N1
,-' N/ N'
N H H H
\ \ \N--...._
N--- /-----/
/---/ /---/
HN -,... HN HN
L...
\
\
N)Y ,
364 ,--
0 NHF 365 )-----NH F 366
NH N\ NH
I I'l z., OXi 1µ1,..,..H F
"N \ N \ N
N( Ni
N/
H H H
N-.....
N---._ /------/ /----/
,.. 9 HN HN
HN
0
\
367 OINH - \ 368 0 NH F ----- \ 369 0 NH
F
N \ NH N
===,õ \ NH
I I
\N \ N "N
N/ N/ N/
H H H
\N....-.._ \ H
N.--,
/--....../ /----- e-"---0
0
HN
/ N
\ CI) HN /
/ N
\
HN 372 )NHF .....,_,
370 HN
F 371 F --..._
NH
N \
\N I N
N/ Ni H
H
H
H H H
i N--.s_/
4,----s0 --))9'---0 r". //-=0
0 0 0
------)`--- / N
\ / N
\ / N
\
F
373 0 NH F .-.,. 374 H2N F --...._ 375
N \ NH
NH
N / \ N \ N
I \ N
N/ Ni
H H H
43

CA 02853703 2014-04-25
WO 2013/151708
PCT/US2013/031055
/
H V H H , N-e
o o
/ \
/ N
\
376 F , 377 F , 378
C-
N -----
N\ NH ...,, N\ NH
I \ NH
--...õ
II
I N õ---
N 7'
N
'.-...."-Nt
N/ N
H H
H
H , H H
0
0 0 0
\--'- N
\ 1 \
379 ....._ 380 , 381 0 NH F
0.'-'NH F
N\ NH N\ NH , \ \ NH
-,,,, 0.'-'N,,,H F
I
.1 N
NI õ..... N ,, \
\ \N 7 ,N 1
INI' N
N H
H _ H
H
H H ,
,
9 5
0
/ \
/ N / N
NI
\
\ \ 7- F
382 0 NH F 383 ----NH F , 384
N\ NH
N\ NH N \ NH ,,,...
--....,
I
NI I N
N 7-= \N
\N \ N
/ 11/
N N H H H.
. ii , H , hi
N--c, N--õ7 N- /
oer'-'0 ( 0//-'-'-0 0//S.'
."--,
0 N
\ a . FA-p
1
0NH F
NH
385 F 386 387
N\
NH \ NH
\
\N
NiN N
14/
N/ H
H
H
H ,
- H , H ,
0
0 0
388 1
0 NH,.
/ \
.s.._ N
\
389 [-,
...---.
0 F NH N
q 0 390 -Y.
NH F
N\ NH
H N \ NH N\ NH ,..õ,
I
N ,--
\ ,N1
iN
14.
N
N H H H
H H " , H
0
0
42 N
\
391 I
0 NH F / N
---- \ 392 0 NH F
N ---- 393 0 NH F
N\ NH
NH -.õ,.
N
\ N \N
N/ Ni
H H H
44

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
H ,
N---/
0
[ \ S
N (;11 / N 0 NH
\ \ N\ NH
HN
394 F HN
NH , 395 396
NI
N \ NH
N
\ \
I I /NI
\ \
N H
,N
N'
N
H Fl
c \ / N
\
NH2 --___, -..._
0 NH N\ NH \ NH
397 õ N \ NH 398
Is
,I , 399 ,,,
i /
\ N
\ N N'
Ni
Ni
H H
H
\
S \ HN
N\ NH N\ NH N\ NH
,,.
401 ,, 402
400 ,----,--
11 I I
N /
N
Ni NiN
H H H
/ N
S \ 0NH 0='-,
NH
, s \
, 403 o NH ---,
N\ NH N\ NH 404 ,,, 405 N
\ NH
r- N
N
I
\N
1 \ N N N
H H
H
0
\ S
NH
.,-- --i
\
0 NH ......, N \ NH N \ NH
406 N 407 \ NH I ''''' 408
,, N _.
NI / N ./
\N \ N
!sr
N N
N/ H H
H
0
(s \ / N / \ N
\ ON S
¨..... \
>)-,
, 0 NH
N\ NH N \ NH Ni 1
410 411 \ NH
409
N \ \
\ N N N
N/ N N
H H H
&
\ S \ ONH ,
0====NH O'NH N\ NH
412 , N \ NH 413 ., N\ NH 414
\N
\ N \ N 1,1/
N/ 14' H
H H
45 n

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
0
I NH t\
S \ \ S \
0 NH s H N ,
415 , N \ NH 416 , --.. N \ NH 417
NI ,, NI I
N /
\N \ N/ N \ N
N,
Ni
H H H
0 / \ / N C-1'1 / \ / N
0 NH F
\
HN S \ HN,1, S \
418 N
\ NH 419
r N ----
\ NH 420
N
\ N
/NI
NI
/11
N
N H H
H
j \/ N
F- F- \
F s \ NH2
0NH -...... N I 423 N \ NH
I I
421 ,.,. N \ NH 422
I N
/I" \
N N N/N
H H H
j \ /
\
F--'s \ HN S \ ---, ---
N ,
N \ NH N \ NH
\ NH
424 425 I ''' 426 rj-
N
N
I N N/
-I Ni H H
H
\ / N / N
a
F s \
0. ,.NH F s 1 0NH F---Cs)---p\ -_,...
.,'
N\ NH 429 NH
N N
427 -.. \ NH 428
NI / N .-
\ N
N
14/
H H H
F--C s / N
NH
\
/ N ,
0,...,...NH F
/N
-__ 14/ ---T N \ NH
430
\N N\ N 11
H 431 \ NH 432
fTh
I
,.,
\
N/ H H
H
ON F s 1 `,...--N S \ F
NH ),--.....1)
434
,
0
N \ NH \
\ Nµ,_,NH
433 I 435 N NH
1
\ N
\ N
/N
NI NI/
N H H H
46

CA 02853703 2014-04-25
WO 2013/151708 PCT/US2013/031055
-,
/ N .... __, \
1 / N y F-(s
\
F s \ ),õ F s 1 0 NH
0NH --,_ 0 NH , N\ NH
1 438 r.,
436 , -, N \ NH 437 ., N \ NH
NI ,_
1,1 N
\
\
N 1 N
\,---N/
11/ H
H H
I
FS
\ F s \
0 NH -__, 0 NH , 0 NH ,
\ NH
N 440 ., N\ NH 441
\ NH
I 1,1 I
N /
\ . \ \
Ni" /4/
N
N/N
H 1-1 H
\
s / N
\
/ N 0,-NH
HN F s \ HN
N \ NH
442 N\ NH 443
.õ
I
NI /. N / \N \
\ 8
N/
iN
N/
N H H H
. N
NH2
), S
N\ NH
0 NH
445 , -, N \ NH 446
I '''' \ NH 447
I
tsj õ,.., N / N ,/
\ \N \
N
/N
N/ Ni
N
H H H
S \ HN
---- \
N\ NH N\ NH ', N\ NH
448
I 449 I '. 450 II
N
N \ N \ N
\N
N/ N/
14/ H H
H
411
S \
0NH Ce'NH ,
0
NH S
\ NH \
----
N
N -,õ, \ NH 453 N
451
r-LI \ NH 452 I ..
NI 7
\ N
\ \N
N/
N H H H
ii
rt1 S \
--- ---.
/ N ,-'NH
S \ ¨.õ
0 NH -, N N\ NH
454 N 455 ,,, \ NH 456 rl
NI ,, N /
N N
\ /,µ
N 1,1/
Ni H H
I-1
47

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PCT/US2013/031055
ON
0 NH
,
N \ NH
458
N
459 Ni\ I
457 r'l
NH
N N
\N \
N/ H N
H H
=,,,,
A \
0INH
S \
OilNIH ,
S \
--_, 0NH
460 ..,. N\ NH 461 N\ NH 462
NI
I \
\ N /N
(,,, N
14/ H
H H
1 A \ / N T
/ N
S \ S \
. 0 NH 0 NH -....,_ 0 NH
463 =., N\ NH 464
(--, N \ NH 465
NI _. I
N / N /
\ \N \N 1
N
H H H
0 \ --Q-c (1111
HN A \
0
,
i S
7 / N
HN --_,
0NH
466 N' I 467 N\ NH 468 --)Y
\ NH \ NH
\N \N \N
14/ N/ N/
H H H
0 0
0
, S i
/
__
/ / v /
N
/ / \
,,NH 1 \
NH2--___.
470 471 N\ NH
469 N \ NH N \ NH .,
I I
N / N N
_/
\ N \ \
N N
1%1/
N N
H H H
0 0 0
/
\
472 N \ NH 273
-..,
N N \ NH 474 N I
, '= \ NH
-,,
NI
NI
\ \ N
\ N
N/
H H
H
48

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PCT/US2013/031055
o 0 0
Z / N
1
1
NH --- \
0,"-,
NH 0 NH
475 N0
477 N \ NH
476 N\ NH
\ NH
(L'1 I ''''
N ,7 \
N \
N
N
N'
N/ H
H H
0
0
S / S
0NH ,7NH --___ ...._,
,
479 480 N \ NH
478 N \ NH N i
(L' \ NH rµ
N
\
N '1 N/ N
H
H H
O 0 0
ON 1 N 1 \
0 NH
,
,
482 483 N\ NH
N
481 N \ NH \ NH C.L'
\ \/N N
N Ni
N/ N H
H H
O 0 0
-,,
NH
/ S
--.
0,"--NH
.'--, --.. ,
485 486 N \ NH
N O
\ NH
484 N \ NH
,.
I I
N
\ N
N / \ N
\
Ni
/14
Ni
N H H
H
O 0 0
I / S
. , N
1
0 NH ,
487 H N N ,
0 NH 488 0 489 N \ NH N I \ NH -.,
I I
N 7' N ,v
\ N
N
N/
H NI
\.%---N H
H
1
0
V / N
1 / N
1 HN,
492
490 HN --- 491
N \ NH N \ NH N\ NH
-,õ
NI ,-
N
\ ,N \ N
NI' \,7----N Nj
H H H
49

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F
/ N
S s
493 494 N'T
\ NH 495
\ NH
\ NH
NI N N
\N
0
/ N
N
496 N\ NH 497
N\ NH
N
\ N \N
Administration and Pharmaceutical Compositions
[00143] Some embodiments include pharmaceutical compositions comprising:
(a) a safe and therapeutically effective amount of the indazole, or its
corresponding
enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt;
and (b) a
pharmaceutically acceptable carrier.
[00144] The compounds provided herein may also be useful in combination
(administered together or sequentially) with other known agents.
[00145] Non-limiting examples of diseases which can be treated with a
combination of a compound of Formula (I) and other known agents are colorectal
cancer,
ovarian cancer, retinitis pigmentosa, macular degeneration, idiopathic
pulmonary fibrosis
and osteoarthritis.
[00146] In some embodiments, colorectal cancer can be treated with a
combination of a compound of either Fonnula (I) and one or more of the
following
drugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug
leucovorin
(also called folinic acid); Capecitabine (Xeloda ), Irinotecan (Camptosar ),
Oxaliplatin
(Eloxatin ). Examples of combinations of these drugs which could be further
combined
with a compound of either Formula (I) are FOLFOX (5-FU, leucovorin, and
oxaliplatin),
FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU,
oxaliplatin,
and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer,
chemo

CA 02853703 2014-04-25
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with 5-FU or capecitabine combined with radiation may be given before surgery
(neoadjuvant treatment).
[00147] In some embodiments, ovarian cancer can be treated with a
combination of a compound of either Formula (I) and one or more of the
following
drugs: Topotecan, Liposomal doxorubicin (Doxil ), Gemcitabine (Gemzar ),
Cyclophosphamide (Cytoxan ), Vinorelbine (Navelbineg), Ifosfamide (Ifex ),
Etoposide
(VP-16), Altretamine (Hexalen ), Capecitabine (Xeloda ), Irinotecan (CPT-11,
Camptosar ), Melphalan, Pemetrexed (Alimta ) and Albumin bound paclitaxel (nab-
paclitaxel, Abraxane). Examples of combinations of these drugs which could be
further
combined with a compound of either Formula (I) are TIP (paclitaxel [Taxol],
ifosfamide,
and cisplatin), VelP (vinblastine, ifosfamide, and cisplatin) and VIP
(etoposide [VP-16],
ifosfamide, and cisplatin).
[00148] In some embodiments, a compound of either Formula (I) can be used
to treat cancer in combination with any of the following methods: (a) Hormone
therapy
such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone]
analogs
and inhibitors, and others; (b) Ablation or embolization procedures such as
radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave
thermotherapy and
cryosurgery (eryotherapy); (c) Chemotherapy using alkylating agents such as
cisplatin
and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil
and
ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and
mereaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as
vinca
alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and
taxanes; (f)
Chemotherapy using podophyll toxin, etoposide, teniposide and docetaxel; (g)
Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan,
amsacrine,
etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using
cytotoxic
antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin,
valrubicin,
idanthicin, epirubicin, bleomycin, plicamycin and mitomyein; (1) Chemotherapy
using
tyrosine-kinase inhibitors such as Imatinib mesylate (Gleevee , also known as
ST1-571),
Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva ),
Bortezomib
(Velcade ) , tamoxifen , tofacitinib, crizotinib, Bel-2 inhibitors (e.g.
obatoelax in clinical
trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in
clinical
51

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trials), PI3K inhibitors (eg. perifosine in a phase III trial), VEGF Receptor
2 inhibitors
(e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib,
dabrafenib and
LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-
0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal
antibodies
such as Rituximab (marketed as MabThera or Rituxan ), Trastuzumab (Herceptin
also
known as ErbB2), Cetuximab (marketed as Erbitux ) and Bevacizumab (marketed as
Avastie); and (k) radiation therapy.
100149] In some embodiments, idiopathic pulmonary fibrosis can be treated
with a combination of a compound of either Formula (I) and one or more of the
following
drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under
the brand
name Esbriee), prednisone, azathioprine, N-acetyleysteine, interferon--y lb,
bosentan
(bosentan is currently being studied in patients with 1PF, [The American
Journal of
Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib
(BIBF 1120
and Vargatef), QAX576 [British Journal of Pharmacology (2011), 163(1), 141-
172], and
anti-inflammatory agents such as corticosteroids.
[00150] In some embodiments, a compound of either Formula (I) can be used
to treat idiopathic pulmonary fibrosis in combination with any of the
following methods:
oxygen therapy, pulmonary rehabilitation and surgery.
[00151] In some embodiments, a compound of either Formula (I) can be used
to treat osteoarthritis in combination with any of the following methods: (a)
Nonsteroidal
anti-inflammatory drugs (NSA1Ds) such as ibuprofen, naproxen, aspirin and
acetaminophen; (b) physical therapy; (c) injections of corticosteroid
medications; (d)
injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e)
narcotics, like
codeine; (f) in combination with braces and/or shoe inserts or any device that
can
immobilize or support your joint to help you keep pressure off it (e.g.,
splints, braces,
shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h)
joint
replacement (arthroplasty); and (i) in combination with a chronic pain class.
[00152] In some embodiments, macular degeneration can be treated with a
combination of a compound of either Formula (I) and one or more of the
following
drugs: Bevacizumab (Avastin ), Ranibizumab (Lucentise), Pegaptanib (Macugen),
Aflibercept (Eylea ), verteporfin (Visudyne ) in combination with photodynamic
therapy
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(PDT) or with any of the following methods: (a) in combination with laser to
destroy
abnormal blood vessels (photocoagulation); and (b) in combination with
increased
vitamin intake of antioxidant vitamins and zinc.
[00153] In some embodiments, retinitis pigmentosa can be treated with a
combination of a compound of either Formula (I) and one or more of the
following
drugs: UF-021 (OcusevaTm), vitamin A palmitate and pikachurin or with any of
the
following methods: (a) with the Argus II retinal implant; and (b) with stem
cell and/or
gene therapy.
[00154] Administration of the compounds disclosed herein or the
pharmaceutically acceptable salts thereof can be via any of the accepted modes
of
administration for agents that serve similar utilities including, but not
limited to, orally,
subcutaneously, intravenously, intranasally, topically, transdermally,
intraperitoneally,
intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-
otologically,
intraocularly, subconjuctivally, via anterior eye chamber injection,
intravitreally,
intraperitoneally, intrathecally, intracystically, intrapleurally, via wound
irrigation,
intrabuccally, intra-abdominally, intra-articularly, intra-aurally,
intrabronchially,
intracapsularly, intrameningeally, via inhalation, via endotracheal or
endobronchial
instillation, via direct instillation into pulmonary cavities, intraspinally,
intrasynovially,
intrathoracically, via thoracostomy irrigation, epidurally, intratympanically,
intracisternally, intravascularly, intraventricularly, intraosseously, via
irrigation of
infected bone, or via application as part of any admixture with a prosthetic
devices. Oral
and parenteral administrations are customary in treating the indications.
[00155] Compounds provided herein intended for phalli aceutical use may be
administered as crystalline or amorphous products. Pharmaceutically acceptable
compositions may include solid, semi-solid, liquid, solutions, colloidal,
liposomes,
emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms,
such as,
e.g., tablets, capsules, powders, liquids, suspensions, suppositories,
aerosols, implants,
controlled release or the like. They may be obtained, for example, as solid
plugs,
powders, or films by methods such as precipitation, crystallization, milling,
grinding,
supercritical fluid processing, coacervation, complex coacervation,
encapsulation,
emulsification, complexation, freeze drying, spray drying, or evaporative
drying.
53

CA 02853703 2015-11-09
60412-4774
Microwave or radio frequency drying may be used for this purpose. The
compounds can
also be administered in sustained or controlled release dosage forms,
including depot
injections, osmotic pumps, pills (tablets and or capsules), transdermal
(including
electrotransport) patches, implants and the like, for prolonged and/or timed,
pulsed
administration at a predetermined rate.
[00156] The compounds can be administered either alone or more typically in
combination with a conventional pharmaceutical carrier, excipient or the like.
The term
"excipient" is used herein to describe any ingredient other than the
compound(s) provided
herein. Pharmaceutically acceptable excipients include, but are not limited
to, ion
exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug
delivery systems
(SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants
used in
TM
pharmaceutical dosage forms such as Tweens, poloxamers or other similar
polymeric
delivery matrices, serum proteins, such as human serum albumin, buffer
substances such
as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate,
disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride,
zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,
cellulose-based
substances, polyethylene glycol, sodium carboxymethyl cellulose,
polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such
as a-,
13, and y-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-b-cyclodextrins,
or other
solubilized derivatives can also be advantageously used to enhance delivery of
compounds described herein. Dosage forms or compositions containing a compound
as
described herein in the range of 0.005% to 100% with the balance made up from
non-
toxic carrier may be prepared. The contemplated compositions may contain
0.001%-
100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-
85%, in
a further embodiment 20-80%, Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for example, see
Remington: The
Science and Practice of Pharmacy, 22"d Edition (Pharmaceutical Press, London,
UK.
2012).
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[00157] In one preferred embodiment, the compositions will take the form of a
unit dosage form such as a pill or tablet and thus the composition may
contain, along with
the active ingredient, a diluent such as lactose, sucrose, dicalcium
phosphate, or the like;
a lubricant such as magnesium stearate or the like; and a binder such as
starch, gum
acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the
like. In
another solid dosage form, a powder, marume, solution or suspension (e.g., in
propylene
carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is
encapsulated in a
capsule (gelatin or cellulose base capsule). Unit dosage forms in which the
two active
ingredients are physically separated are also contemplated; e.g., capsules
with granules
(or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel
caps, etc.
Enteric coated or delayed release oral dosage forms are also contemplated.
[00158] Liquid pharmaceutically administrable compositions can, for example,
be prepared by dissolving, dispersing, etc. an active compound as defined
above and
optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous
dextrose,
glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome,
emulsion,
complexes, coacervate or suspension. If desired, the pharmaceutical
composition can also
contain minor amounts of nontoxic auxiliary substances such as wetting agents,
emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and
the like
(e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan
monolaurate,
triethanolamine acetate, triethanolamine oleate, and the like).
[00159] In some embodiments, the unit dosage of compounds of Formula (I) is
0.25 mg/Kg to 50 mg/Kg in humans.
[00160] In some embodiments, the unit dosage of compounds of Formula (I) is
0.25 mg/Kg to 20 mg/Kg in humans.
[00161] In some embodiments, the unit dosage of compounds of Formula (I) is
0.50 mg/Kg to 19 mg/Kg in humans.
[00162] In some embodiments, the unit dosage of compounds of Formula (I) is
0.75 mg/Kg to 18 mg/Kg in humans.
[00163] In some embodiments, the unit dosage of compounds of Formula (I) is
1.0 mg/Kg to 17 mg/Kg in humans.

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[00164] In some embodiments, the unit dosage of compounds of Formula (I) is
1.25 mg/Kg to 16 mg/Kg in humans.
[00165] In some embodiments, the unit dosage of compounds of Formula (I) is
1.50 mg/Kg to 15 mg/Kg in humans.
[00166] In some embodiments, the unit dosage of compounds of Formula (I) is
1.75 mg/Kg to 14 mg/Kg in humans.
[00167] In some embodiments, the unit dosage of compounds of Formula (I) is
2.0 mg/Kg to 13 mg/Kg in humans.
[00168] In some embodiments, the unit dosage of compounds of Formula (I) is
3.0 mg/Kg to 12 mg/Kg in humans.
[00169] In some embodiments, the unit dosage of compounds of Foimula (I) is
4.0 mg/Kg to 11 mg/Kg in humans.
[00170] In some embodiments, the unit dosage of compounds of Formula (I) is
5.0 mg/Kg to 10 mg/Kg in humans.
[00171] In some embodiments, the compositions are provided in unit dosage
forms suitable for single administration of a precise dose.
[00172] In some embodiments, the compositions are provided in unit dosage
folnis suitable for twice a day administration of a precise dose.
[00173] In some embodiments, the compositions are provided in unit dosage
forms suitable for three times a day administration of a precise dose.
[00174] Injectables can be prepared in conventional forms, either as liquid
solutions, colloid, liposomes, complexes, coacervate or suspensions, as
emulsions, or in
solid forms suitable for reconstitution in liquid prior to injection. The
percentage of active
compound contained in such parenteral compositions is highly dependent on the
specific
nature thereof, as well as the activity of the compound and the needs of the
subject.
However, percentages of active ingredient of 0.01% to 10% in solution are
employable,
and could be higher if the composition is a solid or suspension, which could
be
subsequently diluted to the above percentages.
[00175] In some embodiments, the composition will comprise 0.1-10% of the
active agent in solution.
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[00176] In some embodiments, the composition will comprise 0.1-5% of the
active agent in solution.
[00177] In some embodiments, the composition will comprise 0.1-4% of the
active agent in solution.
[00178] In some embodiments, the composition will comprise 0.15-3% of the
active agent in solution.
[00179] In some embodiments, the composition will comprise 0.2-2% of the
active agent in solution.
[00180] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-96
hours.
[00181] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-72
hours.
[00182] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-48
hours.
[00183] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-24
hours.
[00184] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-12
hours.
[00185] In some embodiments, the compositions are provided in dosage forms
suitable for continuous dosage by intravenous infusion over a period of 1-6
hours.
[00186] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 5 mg/m2 to 300 mg/m2.
[00187] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 5 mg/m2 to 200 mg/m2.
[00188] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 5 mg/m2 to 100 mg/m2.
[00189] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 10 mg/m2 to 50 mg/m2.
[00190] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 50 mg/m2 to 200 mg/m2.
57

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[00191] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 75 mg/m2 to 175 mg/m2.
[00192] In some embodiments, these compositions can be administered by
intravenous infusion to humans at doses of 100 mg/m2 to 150 mg/m2.
[00193] It is to be noted that concentrations and dosage values may also vary
depending on the specific compound and the severity of the condition to be
alleviated. It
is to be further understood that for any particular patient, specific dosage
regimens should
be adjusted over time according to the individual need and the professional
judgment of
the person administering or supervising the administration of the
compositions, and that
the concentration ranges set forth herein are exemplary only and are not
intended to limit
the scope or practice of the claimed compositions.
[00194] In one preferred embodiment, the compositions can be administered to
the respiratory tract (including nasal and pulmonary) e.g., through a
nebulizer, metered
dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator,
liquid instillation
or other suitable device or technique.
[00195] In some embodiments, aerosols intended for delivery to the nasal
mucosa are provided for inhalation through the nose. For optimal delivery to
the nasal
cavities, inhaled particle sizes of about 5 to about 100 microns are useful,
with particle
sizes of about 10 to about 60 microns being preferred. For nasal delivery, a
larger
inhaled particle size is desired to maximize impaction on the nasal mucosa and
to
minimize or prevent pulmonary deposition of the administered formulation. In
some
embodiments, aerosols intended for delivery to the lung are provided for
inhalation
through the nose or the mouth. For optimal delivery to the lung, inhaled
aerodynamic
particle sizes of about less than 10 um are useful, with an aerodynamic
particle size of
about 1 to about 10 microns being preferred. Inhaled particles may be defined
as liquid
droplets containing dissolved drug, liquid droplets containing suspended drug
particles
(in cases where the drug is insoluble in the suspending medium), dry particles
of pure
drug substance, drug substance incorporated with excipients, liposomes,
emulsions,
colloidal systems, coacervates, aggregates of drug nanoparticles, or dry
particles of a
diluent which contain embedded drug nanoparticles.
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[00196] In some embodiments, compounds of Formula (I) disclosed herein
intended for respiratory delivery (either systemic or local) can be
administered as
aqueous formulations, as non-aqueous solutions or suspensions, as suspensions
or
solutions in halogenated hydrocarbon propellants with or without alcohol, as a
colloidal
system, as emulsions, coacervates or as dry powders. Aqueous formulations may
be
aerosolized by liquid nebulizers employing either hydraulic or ultrasonic
atomization or
by modified micropump systems (like the soft mist inhalers, the Aerodose or
the AERx
systems). Propellant-based systems may use suitable pressurized metered-dose
inhalers
(pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are
capable of
dispersing the drug substance effectively. A desired particle size and
distribution may be
obtained by choosing an appropriate device.
[00197] In some embodiments, the compositions of Formula (1) disclosed
herein can be administered to the ear by various methods. For example, a round
window
catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used.
[001981 Alternatively, formulations can be incorporated into a wick for use
between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed
to collagen
sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).
[00199] If desired, formulations of the invention can be incorporated into a
gel
formulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).
[00200] In some embodiments, compounds of Founula (1) disclosed herein
intended for delivery to the ear can be administered via an implanted pump and
delivery
system through a needle directly into the middle or inner ear (cochlea) or
through a
cochlear implant stylet electrode channel or alternative prepared drug
delivery channel
such as but not limited to a needle through temporal bone into the cochlea.
[00201] Other options include delivery via a pump through a thin film coated
onto a multichannel electrode or electrode with a specially imbedded drug
delivery
channel (pathways) carved into the thin film for this purpose. In other
embodiments the
acidic or basic solid compound of Follnula I can be delivered from the
reservoir of an
external or internal implanted pumping system.
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[00202] Formulations of the invention also can be administered to the ear by
intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S.
Pat. No.
6,377,849 and Ser. No. 11/337,815).
[00203] Intratympanic injection of therapeutic agents is the technique of
injecting a therapeutic agent behind the tympanic membrane into the middle
and/or inner
ear. In one embodiment, the foimulations described herein are administered
directly onto
the round window membrane via transtympanic injection. In another embodiment,
the ion
channel modulating agent auris-acceptable formulations described herein are
administered onto the round window membrane via a non-transtympanic approach
to the
inner ear. In additional embodiments, the formulation described herein is
administered
onto the round window membrane via a surgical approach to the round window
membrane comprising modification of the crista fenestrae cochleae.
[00204] In some embodiments, the compounds of Formula (I) are foimulated
in rectal compositions such as enemas, rectal gels, rectal foams, rectal
aerosols,
suppositories, jelly suppositories, or retention enemas, containing
conventional
suppository bases such as cocoa butter or other glycerides, as well as
synthetic polymers
such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
[00205] Suppositories for rectal administration of the drug (either as a
solution,
colloid, suspension or a complex) can be prepared by mixing the drug with a
suitable
non-irritating excipient that is solid at ordinary temperatures but liquid at
the rectal
temperature and will therefore melt or erode/dissolve in the rectum and
release the drug.
Such materials include cocoa butter, glycerinated gelatin, hydrogenated
vegetable oils,
poloxamers, mixtures of polyethylene glycols of various molecular weights and
fatty acid
esters of polyethylene glycol. In suppository forms of the compositions, a low-
melting
wax such as, but not limited to, a mixture of fatty acid glycerides,
optionally in
combination with cocoa butter is first melted.
[00206] Solid compositions can be provided in various different types of
dosage fauns, depending on the physicochemical properties of the drug, the
desired
dissolution rate, cost considerations, and other criteria. In one of the
embodiments, the
solid composition is a single unit. This implies that one unit dose of the
drug is comprised
in a single, physically shaped solid foini or article. In other words, the
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is coherent, which is in contrast to a multiple unit dosage form, in which the
units are
incoherent.
[00207] Examples of single units which may be used as dosage forms for the
solid composition include tablets, such as compressed tablets, film-like
units, foil-like
units, wafers, lyophilized matrix units, and the like. In a preferred
embodiment, the solid
composition is a highly porous lyophilized form. Such lyophilizates, sometimes
also
called wafers or lyophilized tablets, are particularly useful for their rapid
disintegration,
which also enables the rapid dissolution of the active compound.
[00208] On the other hand, for some applications the solid composition may
also be formed as a multiple unit dosage foul' as defined above. Examples of
multiple
units are powders, granules, microparticles, pellets, mini-tablets, beads,
lyophilized
powders, and the like. In one embodiment, the solid composition is a
lyophilized powder.
Such a dispersed lyophilized system comprises a multitude of powder particles,
and due
to the lyophilization process used in the formation of the powder, each
particle has an
irregular, porous microstructure through which the powder is capable of
absorbing water
very rapidly. resulting in quick dissolution. Effervescent compositions are
also
contemplated to aid the quick dispersion and absorption of the compound.
[00209] Another type of multiparticulate system which is also capable of
achieving rapid drug dissolution is that of powders, granules, or pellets from
water-
soluble excipients which are coated with the drug, so that the drug is located
at the outer
surface of the individual particles. In this type of system, the water-soluble
low molecular
weight excipient is useful for preparing the cores of such coated particles,
which can be
subsequently coated with a coating composition comprising the drug and,
preferably, one
or more additional excipients, such as a binder, a pore former, a saccharide,
a sugar
alcohol, a film-forming polymer, a plasticizer, or other excipients used in
pharmaceutical
coating compositions.
[00210] Also provided herein are kits. Typically, a kit includes one or more
compounds or compositions as described herein. In certain embodiments, a kit
can
include one or more delivery systems, e.g., for delivering or administering a
compound as
provided herein, and directions for use of the kit (e.g., instructions for
treating a patient).
In another embodiment, the kit can include a compound or composition as
described
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herein and a label that indicates that the contents are to be administered to
a patient with
cancer. In another embodiment, the kit can include a compound or composition
as
described herein and a label that indicates that the contents are to be
administered to a
patient with one or more of hepatocellular carcinoma, colon cancer, leukemia,
lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis,
rheumatoid arthritis, sclerodeima, mycotic and viral infections, bone and
cartilage
diseases, Alzheimer's disease, lung disease, osteoarthritis, polyposis coli,
bone density
and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG),
familial
exudative vitreoretinopathy, retinal angiogenesis, early coronary disease,
tetra-amelia,
llerian-duct regression and virilization, SERKAL syndrome, type II diabetes,
Futhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel ph ocomelia syndrome,
odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal
duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dellnal
hypoplasia,
autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX)
syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi
syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.The
actual dose of the active compounds of the present invention depends on the
specific
compound, and on the condition to be treated; the selection of the appropriate
dose is well
within the knowledge of the skilled artisan.
Methods of Treatment
[00211] The compounds and compositions provided herein can be used as
inhibitors and/or modulators of one or more components of the Wnt pathway,
which may
include one or more Wnt proteins, and thus can be used to treat a variety of
disorders and
diseases in which aberrant Wnt signaling is implicated, such as cancer and
other diseases
associated with abnormal angiogenesis, cellular proliferation, and cell
cycling.
Accordingly, the compounds and compositions provided herein can be used to
treat
cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular
proliferation, to
correct a genetic disorder, and/or to treat a neurological
condition/disorder/disease due to
mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt
signaling
components. Non-limiting examples of diseases which can be treated with the
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compounds and compositions provided herein include a variety of cancers,
diabetic
retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic
and viral
infections, bone and cartilage diseases, neurological conditions/diseases such
as
Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neurone
disease,
multiple sclerosis or autism, lung disease, osteoarthritis, polyposis coli,
bone density and
vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG),
familial
exudative vitreoretinopathy, retinal angiogenesis, early coronary disease,
tetra-amelia,
MUllerian-duct regression and virilization, SERKAL syndrome, type II diabetes,
Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,
odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal
duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal
hypoplasia,
autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX)
syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi
syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
[00212] With respect to cancer, the Wnt pathway is known to be constitutively
activated in a variety of cancers including, for example, colon cancer,
hepatocellular
carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer
and leukemias
such as CML, CLL and T-ALL. The constitutive activation is due to
constitutively active
f3-catenin, perhaps due to its stabilization by interacting factors or
inhibition of the
degradation pathway. Accordingly, the compounds and compositions described
herein
may be used to treat these cancers in which the Wnt pathway is constitutively
activated.
In certain embodiments, the cancer is chosen from hepatocellular carcinoma,
colon
cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
[00213] Other cancers can also be treated with the compounds and
compositions described herein.
[00214] More particularly, cancers that may be treated by the compound,
compositions and methods described herein include, but are not limited to, the
following:
[00215] 1) Breast cancers, including, for example ER + breast cancer, ER
breast
cancer, her2.- breast cancer, her2+ breast cancer, stromal tumors such as
fibroadenomas,
phyllodes tumors, and sarcomas, and epithelial tumors such as large duct
papillomas;
carcinomas of the breast including in situ (noninvasive) carcinoma that
includes ductal
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carcinoma in situ (including Paget's disease) and lobular carcinoma in situ,
and invasive
(infiltrating) carcinoma including, but not limited to, invasive ductal
carcinoma, invasive
lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular
carcinoma, and invasive papillary carcinoma; and miscellaneous malignant
neoplasms.
Further examples of breast cancers can include luminal A, luminal B, basal A,
basal B.
and triple negative breast cancer, which is estrogen receptor negative (ER"),
progesterone
receptor negative, and her2 negative (her2"). In some embodiments, the breast
cancer may
have a high risk Oncotype score.
[00216] 2) Cardiac cancers, including, for example sarcoma, e.g.,
angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma;
rhabdomyoma; fibroma; lipoma and teratoma.
[00217] 3) Lung cancers, including, for example, bronchogenic carcinoma,
e.g., squamous cell, undifferentiated small cell, undifferentiated large cell,
and
adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma;
sarcoma;
lymphoma; chondromatous hamartoma; and mesothelioma.
[002181 4) Gastrointestinal cancer, including, for example, cancers of the
esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and
lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and
leiomyosarcoma;
cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma,
gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g.,
adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma,
hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel,
e.g.,
adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.
[00219] ) Genitourinary tract cancers, including, for example, cancers of the
kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and
leukemia;
cancers of the bladder and urethra, e.g., squamous cell carcinoma,
transitional cell
carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma,
and
sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma,
teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma,
fibroma,
fibroadenoma, adenomatoid tumors, and lipoma.
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[00220] 6) Liver cancers, including, for example, hepatoma, e.g.,
hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angio sarcoma;
hepatocellular adenoma; and hemangioma.
[00221] 7) Bone cancers, including, for example, osteogenic sarcoma
(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma,
Ewing's
sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,
malignant
giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses),
benign
chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell
tumors.
[00222] 8) Nervous system cancers, including, for example, cancers of the
skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis
defotnians; cancers
of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers
of the
brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma
(pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma,
and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma,
meningioma,
glioma, and sarcoma.
[00223] 9) Gynecological cancers, including, for example, cancers of the
uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical
carcinoma, and
pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma,
including
serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified
carcinoma,
granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and
malignant
teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial
carcinoma,
adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear
cell
carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal
rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.
[00224] 10) Hematologic cancers, including, for example, cancers of the
blood,
e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic
leukemia,
chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma,
and
myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma
(malignant
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[00225] 11) Skin cancers and skin disorders, including, for example, malignant
melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma,
moles
dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.
1002261 12) Adrenal gland cancers, including, for example, neuroblastoma.
[002271 Cancers may be solid tumors that may or may not be metastatic.
Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the tem,
"tumor cell,"
as provided herein, includes a cell afflicted by any one of the above
identified disorders.
[00228] A method of treating cancer using a compound or composition as
described herein may be combined with existing methods of treating cancers,
for example
by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some
embodiments, a
compound or composition can be administered before, during, or after another
anticancer
agent or treatment.
[00229] The compounds and compositions described herein can be used as
anti-angiogenesis agents and as agents for modulating and/or inhibiting the
activity of
protein kinases, thus providing treatments for cancer and other diseases
associated with
cellular proliferation mediated by protein kinases. For example, the compounds
described
herein can inhibit the activity of one or more kinases. Accordingly, provided
herein is a
method of treating cancer or preventing or reducing angiogenesis through
kinase
inhibition.
[00230] In addition, and including treatment of cancer, the compounds and
compositions described herein can function as cell-cycle control agents for
treating
proliferative disorders in a patient. Disorders associated with excessive
proliferation
include, for example, cancers, scleroderma, immunological disorders involving
undesired
proliferation of leukocytes, and restenosis and other smooth muscle disorders.
Furthermore, such compounds may be used to prevent de-differentiation of post-
mitotic
tissue and/or cells.
[00231] Diseases or disorders associated with uncontrolled or abnormal
cellular proliferation include, but are not limited to, the following:
= a variety of cancers, including, but not limited to, carcinoma,
hematopoietic
tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage,
tumors of mesenchymal origin, tumors of the central and peripheral nervous
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system and other tumors including melanoma, seminoma and Kaposi's
sarcoma.
= a disease process which features abnormal cellular proliferation, e.g.,
benign prostatic hyperplasia, familial adenomatosis polyposis,
neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis
following angioplasty or vascular surgery, inflammatory bowel disease,
transplantation rejection, endotoxic shock, and fungal infections. Fibrotic
disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis;
lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis;
glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal
fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those
occurring in the abdomen, pelvis, spine or tendons; chronic obstructive
pulmonary disease; fibrosis following myocardial infarction; pulmonary
fibrosis; fibrosis and scarring associated with diffuse/interstitial lung
disease; central nervous system fibrosis, such as fibrosis following stroke;
fibrosis associated with neuro-degenerative disorders such as Alzheimer's
Disease or multiple sclerosis; fibrosis associated with proliferative
vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and
radiation fibrosis.
= defective apoptosis-associated conditions, such as cancers (including but
not limited to those types mentioned herein), viral infections (including but
not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and
adenovirus), prevention of AIDS development in HIV-infected individuals,
autoimmune diseases (including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, scleroderma, autoimmune mediated
glomerulonephritis, inflammatory bowel disease and autoimmune diabetes
mellitus), neurodegenerative disorders (including but not limited to
Alzheimer's disease, lung disease, amyotrophic lateral sclerosis, retinitis
pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular
atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic
anemia, ischemic injury associated with myocardial infarctions, stroke and
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reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol
related liver diseases, hematological diseases (including but not limited to
chronic anemia and aplastic anemia), degenerative diseases of the
musculoskeletal system (including but not limited to osteroporosis and
arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple
sclerosis,
kidney diseases and cancer pain.
= genetic diseases due to mutations in Writ signaling components, such as
polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative
vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia
syndrome, Mtillerian-duct regression and virilization, SERKAL syndrome,
diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-
Rothschild/S chinzel phocomelia syndrome, odonto-onycho-dermal
dysplasia, obesity, split-hand/foot malfotination, caudal duplication
syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal
hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-
thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome,
Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann
Syndrome and Rett syndrome.
1002321 Furthermore, the compounds and compositions described herein can
be used to treat neurological conditions, disorders and/or diseases caused by
dysfunction
in the Wnt signaling pathway. Non-limiting examples of neurological
conditions/disorders/diseases which can be treated with the compounds and
compositions
provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis,
ataxia
telangiectasia, attention deficit hyperactivity disorder, auditory processing
disorder,
autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,
Canavan
disease, carpal tunnel syndrome, causalgia, central pain syndrome, central
pontine
myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm,
cerebral
arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy,
cerebral vasculitis,
cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation,
chronic
fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP),
chronic
pain, Coffin¨Lowry syndrome, complex regional pain syndrome, compression
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neuropathy, congenital facial diplegia, corticobasal degeneration, cranial
arteritis,
craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder,
Cushing's
syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome,
Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas
disease, delayed sleep phase syndrome, dementia, dermatomyositis,
developmental
dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome,
dysautonomia,
dyscaleulia, dysgraphia, dyslexia, dystonia, empty sella syndrome,
encephalitis,
encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's
palsy,
erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial
spastic
paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia,
fibromyalgia, Foville's
syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant
cell
inclusion disease, globoid cell leukodystrophy, gray matter heterotopia,
Guillain-Barre
syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial
spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritifbrmis,
herpes
zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly,
Huntington's
disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-
mediated
encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile
phytanic
acid storage disease, infantile Refsum disease, infantile spasms, inflammatory
myopathy,
intracranial cyst, intracranial hypertension, Joubert syndrome, Karak
syndrome, Kearns-
Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome,
Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-
Eaton
myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg)
syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome,
leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou
Gehrig's
disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-
Joseph
disease (Spinocerebellar ataxia type 3), macrencephaly, maeropsia,
megalencephaly,
Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease,
etachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome,
misophonia, mitochondria' myopathy, Mobius syndrome, monomelic amyotrophy,
motor
neurone disease, motor skills disorder, Moyamoya disease,
mueopolysaccharidoses,
multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis,
multiple system
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atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis,
myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants,
myoclonus,
myopathy, myotubular myopathy, myotonia congenital, narcolepsy,
neurofibromatosis,
neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal
ceroid
lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital
Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome,
olivopontocerebellar
atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic
hypotension,
palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,
paraneoplastic
diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher
disease,
periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid
storage
disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly,
post-polio
syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi
syndrome,
primary lateral sclerosis, prion diseases, progressive hemifacial atrophy,
progressive
multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor
cerebri,
Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt
syndrome
type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum
disease,
restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome,
Reye's
syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance,
Sandhoff disease, schizophrenia, Schildeis disease, schizencephaly, sensory
integration
dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjogren's syndrome,
snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors,
spinal muscular
atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-
person
syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis,
subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's
chorea,
syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive
dyskinesia, tardive
dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,
tethered spinal
cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux,
Todd's
paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack,
transmissible spongiform encephalopathies, transverse myelitis, tremor,
trigeminal
neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,
ubisiosis, Von
Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's
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Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease
and
Zellweger syndrome.
[00233] The compounds and compositions may also be useful in the inhibition
of the development of invasive cancer, tumor angiogenesis and metastasis.
[00234] In some embodiments, the disclosure provides a method for treating a
disease or disorder associated with aberrant cellular proliferation by
administering to a
patient in need of such treatment an effective amount of one or more of the
compounds of
Formula (I), in combination (simultaneously or sequentially) with at least one
other
agent.
[00235] In some embodiments, the pharmaceutical composition comprises a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable excipient.
[00236] In some embodiments, the method of treats a disorder or disease in
which aberrant Wnt signaling is implicated in a patient, the method comprises
administering to the patient a therapeutically effective amount of a compound
of Fottnula
(I), or a pharmaceutically acceptable salt thereof.
100237] In some embodiments, the disorder or disease is cancer.
[00238] In some embodiments, the disorder or disease is diabetic retinopathy.
[00239] In some embodiments, the disorder or disease is pulmonary fibrosis.
[00240] In some embodiments, the disorder or disease is rheumatoid arthritis.
[00241] In some embodiments, the disorder or disease is scleroderma.
[00242] In some embodiments, the disorder or disease is a mycotic or viral
infection.
1002431 In some embodiments, the disorder or disease is a bone or cartilage
disease.
[00244] In some embodiments, the disorder or disease is Alzheimer's disease.
[00245] In some embodiments, the disorder or disease is osteoarthritis.
[00246] In some embodiments, the disorder or disease is lung disease
[00247] In some embodiments, the disorder or disease is a genetic disease
caused by mutations in Wnt signaling components, wherein the genetic disease
is
selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial
exudative
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vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia
syndrome,
Miillerian-duct regression and virilization, SERKAL syndrome, diabetes
mellitus type 2,
Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,
odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal
duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal
dermal
hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-
thalassemia
(ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-
Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
[002481 In some embodiments, the patient is a human.
[00249] In some embodiments, the cancer is chosen from: hepatocellular
carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid
leukemia
(CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL),
acute
myeloid leukemia, acute lymphoeytic leukemia, Hodgkin lymphoma, lymphoma,
sarcoma and ovarian cancer.
[00250] In some embodiments, the cancer is chosen from: lung cancer - non-
small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer,
neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer,
retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal
and
squamous cell, skin cancer ¨ melanoma, small intestine cancer, stomach
cancers,
testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal
cancer, vulvar
cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma,
gestational
trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal
carcinoid tumor,
gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus
cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or
spinal cord tumor,
bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer
and adrenal
cortical cancer.
[00251] In some embodiments, the cancer is hepatocellular carcinoma.
[00252] In some embodiments, the cancer is colon cancer.
[00253] In some embodiments, the cancer is breast cancer.
[00254] In some embodiments, the cancer is pancreatic cancer.
[00255] In some embodiments, the cancer is chronic myeloid leukemia (CML).
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1002561 In some embodiments, the cancer is chronic myelomonocytic
leukemia.
[00257] In some embodiments, the cancer is chronic lymphocytic leukemia
(CLL).
[00258] In some embodiments, the cancer is acute myeloid leukemia.
[00259] In some embodiments, the cancer is acute lymphocytic leukemia.
[00260] In some embodiments, the cancer is Hodgkin lymphoma.
[00261] In some embodiments, the cancer is lymphoma.
1002621 In some embodiments, the cancer is sarcoma.
[00263] In some embodiments, the cancer is ovarian cancer.
[00264] In some embodiments, the cancer is lung cancer - non-small cell.
[00265] In some embodiments, the cancer is lung cancer - small cell.
[00266] In some embodiments, the cancer is multiple myeloma.
[00267] In some embodiments, the cancer is nasopharyngeal cancer.
[00268] In some embodiments, the cancer is neuroblastoma.
[00269] In some embodiments, the cancer is osteosarcoma.
1002701 In some embodiments, the cancer is penile cancer.
[00271] In some embodiments, the cancer is pituitary tumors.
[00272] In some embodiments, the cancer is prostate cancer.
[00273] In some embodiments, the cancer is retinoblastoma.
[00274] In some embodiments, the cancer is rhabdomyosarcoma.
[00275] In some embodiments, the cancer is salivary gland cancer.
[00276] In some embodiments, the cancer is skin cancer - basal and squamous
cell.
[00277] In some embodiments, the cancer is skin cancer ¨ melanoma.
1002781 In some embodiments, the cancer is small intestine cancer.
[00279] In some embodiments, the cancer is stomach cancers.
[00280] In some embodiments, the cancer is testicular cancer.
[00281] In some embodiments, the cancer is thymus cancer.
[00282] In some embodiments, the cancer is thyroid cancer.
[00283] In some embodiments, the cancer is uterine sarcoma.
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[00284] In some embodiments, the cancer is vaginal cancer.
[00285] In some embodiments, the cancer is vulvar cancer.
[00286] In some embodiments, the cancer is Wilms tumor.
[00287] In some embodiments, the cancer is laryngeal or hypopharyngeal
cancer.
[00288] In some embodiments, the cancer is kidney cancer.
[00289] In some embodiments, the cancer is Kaposi sarcoma.
[00290] In some embodiments, the cancer is gestational trophoblastic disease.
[00291] In some embodiments, the cancer is gastrointestinal stromal tumor.
[00292] In some embodiments, the cancer is gastrointestinal carcinoid tumor.
[00293] In some embodiments, the cancer is gallbladder cancer.
[00294] In some embodiments, the cancer is eye cancer (melanoma and
lymphoma).
[00295] In some embodiments, the cancer is Ewing tumor.
[00296] In some embodiments, the cancer is esophagus cancer.
[00297] In some embodiments, the cancer is endometrial cancer.
[00298] In some embodiments, the cancer is colorectal cancer.
[00299] In some embodiments, the cancer is cervical cancer.
[00300] In some embodiments, the cancer is brain or spinal cord tumor.
[00301] In some embodiments, the cancer is bone metastasis.
[00302] In some embodiments, the cancer is bone cancer.
[00303] In some embodiments, the cancer is bladder cancer.
[00304] In some embodiments, the cancer is bile duct cancer.
[00305] In some embodiments, the cancer is anal cancer.
[00306] In some embodiments, the cancer is adrenal cortical cancer.
[00307] In some embodiments, the disorder or disease is a neurological
condition, disorder or disease, wherein the neurological
condition/disorder/disease is
selected from: Alzheimer's disease, frontotemporal dementias, dementia with
lewy
bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive
supranuclear palsy, corticobasal degeneration, mutiple system atrophy,
amyotrophic
lateral sclerosis (ALS), inclusion body myositis, autism, degenerative
myopathies,
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diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies,
orthostatic
hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.
[00308] In some embodiments, the compound of Formula (I) inhibits one or
more proteins in the Wnt pathway.
[00309] In some embodiments, the compound of Formula (I) inhibits signaling
induced by one or more Wnt proteins.
[00310] In some embodiments, the Wnt proteins are chosen from: WNTI,
WN. IT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A,
WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and
WNT 16.
[00311] In some embodiments, the compound of Formula (I) inhibits a kinase
activity.
[00312] In some embodiments, the method treats a disease or disorder
mediated by the Wnt pathway in a patient, the method comprises administering
to the
patient a therapeutically effective amount of a compound (or compounds) of
Formula (I),
or a pharmaceutically acceptable salt thereof.
[00313] In some embodiments, the compound of Formula (I) inhibits one or
more Wnt proteins.
[00314] In some embodiments, the method treats a disease or disorder
mediated by kinase activity in a patient, the method comprises administering
to the
patient a therapeutically effective amount of a compound (or compounds) of
Formula (I),
or a pharmaceutically acceptable salt thereof
[00315] In some embodiments, the disease or disorder comprises tumor
growth, cell proliferation, or angiogenesis.
[00316] In some embodiments, the method inhibits the activity of a protein
kinase receptor, the method comprises contacting the receptor with an
effective amount
of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable
salt
thereof.
[00317] In some embodiments, the method treats a disease or disorder
associated with aberrant cellular proliferation in a patient; the method
comprises

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administering to the patient a therapeutically effective amount of a compound
(or
compounds) of Formula (I), or a pharmaceutically acceptable salt thereof
[00318] In some embodiments, the method prevents or reduces angiogenesis in
a patient; the method comprises administering to the patient a therapeutically
effective
amount of a compound (or compounds) of Formula (I), or a pharmaceutically
acceptable
salt thereof.
[00319] In some embodiments, the method prevents or reduces abnormal
cellular proliferation in a patient; the method comprises administering to the
patient a
therapeutically effective amount of a compound (or compounds) of Formula (I),
or a
pharmaceutically acceptable salt thereof
[00320] In some embodiments, the method treats a disease or disorder
associated with aberrant cellular proliferation in a patient, the method
comprises
administering to the patient a phatinaceutical composition comprising one or
more of the
compounds of claim 1 in combination with a pharmaceutically acceptable carrier
and one
or more other agents.
[00321] Moreover, the compounds and compositions, for example, as
inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of
cellular
RNA and DNA synthesis and therefore are expected to be useful in the treatment
of viral
infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr
virus,
adenovirus, Sindbis virus, pox virus and the like.
[00322] Compounds and compositions described herein can inhibit the kinase
activity of, for example, CDK/cyclin complexes, such as those active in the
Go. or G.1
stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes.
Evaluation of Biological Activity
[00323] The biological activity of the compounds described herein can be
tested using any suitable assay known to those of skill in the art, e.g., WO
2001/053268
or WO 2005/009997. For example, the activity of a compound may be tested using
one or
more of the test methods outlined below.
[00324] In one example, tumor cells may be screened for Wnt independent
growth. In such a method, tumor cells of interest are contacted with a
compound (i.e.
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inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of
tritiated
thymidine, is monitored. In some embodiments, tumor cells may be isolated from
a
candidate patient who has been screened for the presence of a cancer that is
associated
with a mutation in the Wnt signaling pathway. Candidate cancers include,
without
limitation, those listed above.
[00325] In another example, one may utilize in vitro assays for Wnt biological
activity, e.g. stabilization of 13-catenin and promoting growth of stem cells.
Assays for
biological activity of Wnt include stabilization of p-catenin, which can be
measured, for
example, by serial dilutions of a candidate inhibitor composition. An
exemplary assay for
Wnt biological activity contacts a Wnt composition in the presence of a
candidate
inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period
of time
sufficient to stabilize P-catenin, usually at least about 1 hour, and lysed.
The cell lysate is
resolved by SDS PAGE, then transferred to nitrocellulose and probed with
antibodies
specific for P-catenin.
[00326] In a further example, the activity of a candidate compound can be
measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997),
88(6), 747-
756).
[00327] To further illustrate this invention, the following examples are
included. The examples should not, of course, be construed as specifically
limiting the
invention. Variations of these examples within the scope of the claims are
within the
purview of one skilled in the art and are considered to fall within the scope
of the
invention as described, and claimed herein. The reader will recognize that the
skilled
artisan, armed with the present disclosure, and skill in the art is able to
prepare and use
the invention without exhaustive examples.
EXAMPLES
Compound preparation
[00328] The starting materials used in preparing the compounds of the
invention are known, made by known methods, or are commercially available. It
will be
apparent to the skilled artisan that methods for preparing precursors and
functionality
related to the compounds claimed herein are generally described in the
literature. The
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CA 02853703 2015-11-09
60412-4774
skilled artisan given the literature and this disclosure is well equipped to
prepare any of
the compounds.
[00329] It is recognized that the skilled artisan in the art of organic
chemistry
can readily carry out manipulations without further direction, that is, it is
well within the
scope and practice of the skilled artisan to carry out these manipulations.
These include
reduction of carbonyl compounds to their corresponding alcohols, oxidations,
acylations,
aromatic substitutions, both electrophilic and nucleophilic, etherifications,
esterification
and saponification and the like. These manipulations are discussed in standard
texts such
as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure
7th Ed.,
John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5th
Ed.,
Springer (2007), Comprehensive Organic Transformations: A Guide to Functional
Group
Transformations, 2nd Ed., John Wiley & Sons (1999)
and the like.
[00330] The skilled artisan will readily appreciate that certain reactions are
best
carried out when other functionality is masked or protected in the molecule,
thus avoiding
any undesirable side reactions and/or increasing the yield of the reaction.
Often the
skilled artisan utilizes protecting groups to accomplish such increased yields
or to avoid
the undesired reactions. These reactions are found in the literature and are
also well
within the scope of the skilled artisan. Examples of many of these
manipulations can be
found for example in T. Greene and P. Wuts Protective Groups in Organic
Synthesis, 4th
Ed., John Wiley & Sons (2007).
[00331] Trademarks used herein are examples only and reflect illustrative
materials used at the time of the invention. The skilled artisan will
recognize that
variations in lot, manufacturing processes, and the like, are expected. Hence
the
examples, and the trademarks used in them are non-limiting, and they are not
intended to
be limiting, but are merely an illustration of how a skilled artisan may
choose to perform
one or more of the embodiments of the invention.
[00332] 1H nuclear magnetic resonance spectra (NMR) were measured in the
indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for
IH). Peak positions are expressed in parts per million (ppm) dovvnfield from
tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet;
d, doublet; t,
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triplet; q, quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd,
doublet of
doublets; td, triplet of doublets; dt, doublet of triplets; in, multiplet.
[00333] The following abbreviations have the indicated meanings:
(Boc)20 = di-tert-butyl dicarbonate
brine = saturated aqueous sodium chloride
CDC13 = deuterated chloroform
CsCO3 = cesium carbonate
DCE = dichloroethane
DCM = dichloromethane
DEAD = diethyl azodicarboxylate
DHP = 3,4-dihydro-2H-pyran
DMF = N,N-dimethylformamide
DMSO-d6 = deuterated dimethylsulfoxide
ESIMS = electron spray mass spectrometry
Et0Ac = ethyl acetate
Et3SiH = triethylsilane
HC1 = hydrochloric acid
HOAc = acetic acid
KOAc = potassium acetate
KOH = potassium hydroxide
K3PO4 = potassium phosphate
LAH = lithium aluminum hydride
Me0H = methanol
MgSO4 = magnesium sulfate
NaBH4 = sodium borohydride
NaBH(OAc)3 = sodium txiacetoxy borohydride
NaCNBH3 = sodium cyanoborohydride
Na2CO3 = sodium carbonate
NaHCO3 = sodium bicarbonate
NaFIS03 = sodium bisulfite
NallSO4 = sodium bisulfate
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Na0Ac = sodium acetate
NMR = nuclear magnetic resonance
ON = overnight
PE = petroleum ether
Pd/C = palladium on carbon
Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0)
Pd(dppf)2C12 = 1 , 1 f-bis(diphenylphosphino)ferrocene-palladium(I)dichloride
Pd(PPh3)2C12 = dichloro-bis(triphenylphosphine)palladium (II)
Pd(PPh3)4 = tetrakis(triphenylphosphine)pal ladi um(0)
PPh3 = triphenylphosphine
PPTS = pyridinium p-toluenesulfonate
rt = room temperature
SEM ¨ 2-(trimethylsilyl)ethoxymethyl
TEA = triethylamine
TFA = trifluoroacetic acid
THE = tetrahydrofuran
TLC = thin layer chromatography
[00334] The following example schemes are provided for the guidance of the
reader, and collectively represent an example method for making the compounds
provided herein. Furthermore, other methods for preparing compounds of the
invention
will be readily apparent to the person of ordinary skill in the art in light
of the following
reaction schemes and examples. The skilled artisan is thoroughly equipped to
prepare
these compounds by those methods given the literature and this disclosure. The
compound numberings used in the synthetic schemes depicted below are meant for
those
specific schemes only, and should not be construed as or confused with same
numberings
in other sections of the application. Unless otherwise indicated, all
variables are as
defined above.

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General procedures
[00335] Compounds of Formula I of the present invention can be prepared as
depicted in Scheme 1.
H 0 0
0
,TO R1-Br IV 121
\N \ N \N
N/
Suzuki
05 03 05
V
p
VI
H2N
NHz
Cyclization 4
Fepl Rz
N, N,
\ NH \ NH
111
\ N
Deprotection
VIII VII05
Scheme I
[00336] Scheme 1 describes a method for preparation of indazole derivatives
(VIII) by first reacting 5-iodo-1-(tetrahydro-2H-pyran-2-y1)-1H-indazole-3-
carbaldehyde
(H) with bis(pinacolato)diboron to form the borate ester (III). Suzuki
coupling with
various bromides (IV) yields indazole derivatives (V). Aldehyde (V) is reacted
with
various 1,2-diamines (VI) to produce (VII). Final deprotection of the pyrazole
nitrogen
yields the desired indazole derivatives (VIII).
[00337] Alternatively, compounds of Formula I of the present invention can be
prepared as depicted in Scheme 2.
81

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0 0
0
Br B r Br
NaNO2, HCI SEM-CI or
N Acetone, 112 DMF p-Ts0H, THE, 14 'SEM or
THP
0 C-20 C , 3h 0 to r.t. h 80 C
IX X XI
Pa(dppOCl2
KOAc, Mlle
110 C, 3 h
\ NH R2-0 IV IV 0
RI 1-12N- R1 o Na-12 121-Br
is_ \,cr'll P-chlora nil Suzuki
'N SEM or 'N SEM or
THP MeCN -"N¨SEM or
THP THP
XIV XIII XII
1. TFA, DCM R2
2. N113, Me0H
\ NH
R1
VIII
Scheme 2
[00338] Scheme 2 describes an alternative method for preparation of indazole
derivatives (VIII) by first formylating 5-bromo-1H-indole (IX) to produce 5-
bromo-1H-
indazole-3-carbaldehyde (X) followed by protection with either SEM-C1 or DHP
to give
the protected aldehyde (XI). Aldehyde (XI) is then reacted with
bis(pinacolato)diboron to
form the borate ester (XII). Suzuki coupling with various bromides (IV) yields
indazole
derivatives (XIII). Aldehyde (XIII) is reacted with various 1,2-diamines (VI)
to produce
(XIV). Final deprotection of the pyrazole nitrogen yields the desired indazole
derivatives
(VIII).
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Illustrative Compound Examples
[00339] Preparation of intermediate (II) is depicted below in Scheme 3.
0
/
COOH o
NHOMe(MOHC1 , N `0---
F3C OO CF3
0 ---
________________________________________________ 3
imidazole, DMF, 65 C 12, DCM r.t.
XV XVI XVII
DHP, PPTS
DCM, refluxed
v
0 0 /
N \
THF, 0 C
05 ob
II XVIII
Scheme 3
Step 1
[00340] 1H-indazole-3-carboxylic acid (XV) (100 g, 617 mmol) in DMF was
treated with carbonyldiimidazole (110 g, 678 mmol) at room temperature until
the
evolution of gas ceased (ca. 15 minutes). The reaction was heated to 60-65 C
for two
hours and then allowed to cool to room temperature. N,O-Dimethylhydroxylamine-
HC1
(66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 C for
3 hours.
The reaction was concentrated to a paste and taken up in DCM, and washed
subsequently
with water and 2N HO. The product could be seen coming out of solution. The
solid
was filtered and rinsed separately with Et0Ac. The Et0Ac and DCM layers were
separately washed with sodium bicarbonate followed by brine, dried over MgSO4
and
concentrated under reduced pressure. The resulting solids were combined,
triturated with
1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-methy1-1H-
indazole-3-carboxainide (XVI) as a white solid (100 g, 487 mmol, 79% yield).
1H NMR
(DMSO-d6) 6 ppm 3.46 (s, 311), 3.69-3.85 (m, 311), 7.13-7.31 (m, 1H), 7.41 (t,
J=7.25
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WO 2013/151708 PCT/US2013/031055
Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for CloHi 1N302 m/z
206
(M+H).
Step 2
[00341] To the N-methoxy-N-methy1-1H-indazole-3-carboxamide (XVI) (20 g,
97.4 mmol) in DCM (1 L) was added bis(trifluoroacetoxy)iodobenzene (46 g, 107
mmol)
followed by portionwise addition of iodine (14.84 g, 58.5 mmol) at room
temperature.
After 1 hour, 600 niL of saturated NallS03 was added and a solid began to
precipitate
which was filtered and rinsed with excess DCM. The filtrate was washed with
brine,
dried over MgSO4, concentrated and the remaining solid was triturated with a
minimal
amount of DCM. The combined solids were dried under vacuum over KOH to produce
5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (XVII) as a white solid
(23.2
g, 70 mmol, 72% yield). 11--INMR (DMSO-d6) 6 ppm 3.45 (s, 4H), 3.77 (s, 4H),
7.45-7.54
(m, 1H), 7.66 (dd, J-8.81, 1.51 Hz, 1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found
for
C1011101N302 ni/z 331 (M+H).
Step 3
[00342] A mixture of 5 -iodo-N-
methoxy-N-methy1-1H-indazole-3 -
carboxamide (XVII) (16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol)
and
PPTS (0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 hours. The solution
was
poured into a saturated NaHCO3 solution, the layers were separated, and the
aqueous
layer was extracted with DCM. The combined organic layers were washed with 5%
aqueous citric acid and brine, dried over MgSat, and concentrated. The crude
product
was purified on a silica gel column (100% Et0Ac ---> 3:97 MeOH:DCM) to provide
5-
io do-N-methoxy-N-methyl-1 -(tetrahydro-2H-pyran-2-y1)-1H-indazole-3-
carboxamide
(XVIII) as a white viscous oil (19.1 g, 46 mmol, 92% yield). 1H NMR (DMSO-d6)
6 PPm
1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5.86-6.08 (m, 1H), 7.45-7.87
(m,
8.39 (s, 111); ESIMS found for Ci5Hi8IN303 nilz 416 (M+H).
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Step 4
[00343] Lithium aluminum hydride (160 mg, 4.21 mmol) was added in
portions to a cooled (0 C) solution of 5-iodo-N-methoxy-N-methy1-1-(tetrahydro-
2H-
pyran-2-y1)-1H-indazole-3-carboxamide (XVIII) (1.46 g, 3.5 mmol) in THF.
Stirring
was continued at 0 C until the reaction was completed, approximately 30 min.
The
reaction was quenched by the slow addition of Et0Ac at 0 C, and the whole
mixture was
poured into 0.4 N NaHSO4. The organic layer was washed with brine, dried over
MgSO4, concentrated, and purified on a silica gel column (100% Et0Ac 3:97
MeOH:DCM) to give 5-iodo-1-(tetrahydro-2H-pyran-2-y1)-1H-indazole-3-
carbaldehyde
(II) as a white solid (0.90 g, 3.15 mmol, 72% yield). 11-1 NMR (DMSO-d6) 6 ppm
1.50-
1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m, 1H), 3.66-
3.99 (m,
2H), 5.96-6.17 (m, 1H), 7.78 (d, ,7=6 Hz, 1H), 7.84 (d, ./=6 Hz, 1H), 8.50 (s,
1H), 10.13
(s, 1II); ESIMS found for C13H131N202 in/z 357 (M+H).
[00344] Preparation of SEM protected intermediate (XX) is depicted below in
Scheme 4.
0 0
Br Br Br
NaNO2, HCI \ N SEM-CI
NaH, DMF tõ,\
Acetone,H20
0-20 C, 3 h H 0 to r.t. 1 h N \SEM
LX X XIX
7\-0
Pd(dpPf)Cl2
KOAc, DMF
110 C, 3 h
0
0
N
SEM
XX
Scheme 4

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WO 2013/151708 PCT/1JS2013/031055
Step 1
[00345] A solution of NaNO2 (110.4 g, 1.6 mol, 8 eq) in water (200 mL) was
added dropwise to a solution of 5-bromoindole (IX) (39.2 g, 0.2 mol, 1 eq) in
acetone
(1000 mL) stirred at -10--->43 C, while adding NaNO2 the solution temperature
was
maintained below 20 C. An aqueous 2N HC1 solution (480 mL) was added slowly to
the
solution with vigorously stirring while keeping the internal temperature
between 0 and
20 C. The solution was further stirred at 20 C for 3 h after the addition. The
solution was
concentrated under reduced pressure to remove acetone while keeping the
temperature
below 35 C. The solid was collected by filtration and transferred to a flask.
Cold (-10 C)
DCM (200 mL) was added and stirred for 30 min at -5 C, the solids were
filtered and
dried under vacuum at 40 C to get 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0
g, 151
mmol, 76% yield) as a brown solid. ESIMS found for C8H5BrN20 m/z 225 (M+H).
Step 2
[00346] To a suspension of NaH (6.6 g, 166 mmol, 1.10 eq) in DMF (500 mL)
was added a solution of 5-bromo-1H-indazole-3-carbaldehyde (X) (34.0 g, 151
mmol,
1.00 eq) in DMF (50 mL) dropwise at 0 C over a period of 30 min. The mixture
was
stirred at room temperature for 2 h, then SEM-C1 (26.4 g, 159 mmol, 1.08 eq)
was added
dropwise and the mixture was stirred at room temperature for another 3 h. Then
the
mixture was poured into an ice-water mixture (1000 mL) and extracted with
Et0Ac (300
mL x 3), the organic phases were combined, dried over Na2SO4, filtered and
concentrated
in vacuo, the resultant residue was purified by flash chromatography on silica
gel
(PE: Et0Ac = .. 1) to afford 5-bromo-1-42-(trimethylsilyl)ethoxy)methyl)-1H-
indazole-3-carbaldehyde (XIX) as a mixture of regioisomers (53.0 g, 151 mmol,
100%
yield) as a yellow oil. ESIMS found for C14H19BrN202Si m/z 355 (M+H).
Step 3
[00347] To a solution of the mixed 5-bromo-1-42-(trimethylsilyl)ethoxy)
methyl)-1H-indazole-3-carbaldehyde (XIX) (53.0 g, 151 mmol, 1.0 eq),
bis(pinacolato)diboron (38.0 g, 150 mmol, 1.0 eq) and KOAc (44.0 g, 450 mmol,
3.00
86

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eq) in DMF (1000 mL) was added Pd(dppf)C12 (7.7 g, 10.5 mmol, 0.07 eq). The
mixture
was stirred at 90 C under nitrogen for 10 h. The mixture was filtered; the
filtrate was
poured onto water (1000 mL) and extracted with Et0Ac (500 mL x 3). The
combined
organic phases were dried, filtered and concentrated in vacuo. The resultant
residue was
purified by flash chromatography on silica gel (PE:Et0Ac = 10:1¨>1:1) to give
the 5-
(4,4,5,5-tetramethy1-1,3,2-dioxaborol an-2-y1)-142-(trimethylsily1)
ethoxy)methyl)-1H-
indazole-3-carbaldehyde (XX) as a mixture of regioisomers (42.9 g, 106 mmol,
71%
yield) as a yellow oil. ESIMS found for C20H31BN204Si inlz 403 (M+H).
1003481 Preparation of THP protected intermediate (XXI) is depicted below in
Scheme 5.
0 0 0
H
Br Na Br Br
NO2, HC1 3 \ N
Acetone,H200
p-Ts0H, ULF,
-20 C, 3 h
80 C
IX X XXI
Scheme 5
Step 1
(003491 Procedure can be found in Scheme 4, Step 1.
Step 2
[00350] Procedure can be found in Scheme 3, Step 3. 5-Bromo-1-(tetrahydro-
214-pyran-2-y1)-3a,7a-dihydro-1H-indazole-3-carbaldehyde XXI was isolated as a
white
solid (16.4 g, 52.7 mmol, 39.6% yield). 1HNMR (DMSO-d6, 500 MHz) 6 ppm 1.57-
1.65
(m, 211), 1.72-1.83 (m, 1H), 2.02-2.11 (m, 2H), 2.33-2.44 (m 1H), 3.76-3.83
(m, 1H),
3.84-3.93 (m, 114), 6.08 (dd, ./=2.5Hz, 9Hz, 1H), 7.72 (dd, J=1.5Hz, J=8.5Hz,
1H), 7.92
(d, ,J=9Hz, 1H), 8.28 (d, J=21Iz, 111), 10.17 (s, 1H); ESIMS found
C13H15BrN202 m/z
311.0 (M+H).
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[00351] Preparation of inteimediate N-(5-bromopyridin-3-yl)isobutyramide
(XXIV) is depicted below in Scheme 6.
Pyridine
0 C-r.t., 15 h
0
XXII XXIII XXIV
Scheme 6
Step 1
[00352] 3-Amino-5-bromo pyridine (XXII) (1 eq) was dissolved in DCM and
cooled to 0 C before adding pyridine (2.2 eq) and isobutyryl chloride (XXIII)
(1.1 eq).
The reaction mixture was stirred at room temperature for 15 h until TLC showed
the
reaction was complete. The reaction mixture was diluted with DCM and washed
with
water. The organic extract was dried, concentrated and purified by column
chromatography using silica gel (100-200 mesh) to afford N-(5-bromopyridin-3-
yl)isobutyramide (XXIV) as an off-white solid, (71% yield). 1H NMR (CDC13) 6
ppm
8.55-8.35 (m, 311), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS
found
C91111BrN20 m/z 243.05(M+H).
[00353] The following compounds were prepared in accordance with the
procedure described in the above Scheme 6.
XXV
[00354] N-(5-Bromopyridin-3-yl)propionamide (XXV): Off white solid (92%
yield). 1H NMR (DMSO-d6) 6 ppm 1.09 (t, J=7.54 Hz, 311), 2.36 (q, J=7.54 Hz,
2I1),
8.36 (m, 2H), 8.65 (d, J=2.07 Hz, 1H), 10.26 (s, 111); ESIMS found C8119BrN20
adz 231
(M+H).
o
XXVI
88

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[00355] N-(5-Bromopyridin-3-yl)butyramide (XXVI): Yellow solid (2,1 g,
8.64 mmol, 88.8% yield). ESIMS found C9H11BrN20 m/z 243 (M+H).
XXVH
[00356] N-(5-Bromopyridin-3-yl)pentanamide (XXVII): Yellow solid (2.0 g,
7.78 mmol, 85.3% yield). ESIMS found C10H13BrN20 inlz 257 (M+H).
0
XXVHI
[00357] N-(5-Bromopyridin-3-y1)-3-methylbutanamide (XXVIII): Off white
solid, (67% yield), 1H NMR (CDC13, 500 MHz) 6 ppm 8.55-8.42 (m, 3H), 7.62 (s,
1H),
2.31-2.18 (m, 3H), 1.02-1.01 (d, J 6Hz, 6H); ESIMS found C10H13BrN20 m/z
258.80
(M+H).
õBr
XXIX
[00358] N-(5-Bromopyridin-3-y1)-3,3-dimethylbutanamide (XXIX): Yellow
solid (1.7 g, 6.27 mmol, 78.6% yield). ESIMS found C11H15BrN20 m/z 271 (M+H).
voc
[00359] N-(5-Bromopyridin-3-yl)pivalamide (XXX): Off-white solid (1.082 g,
4.22 mmol, 73.1% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.23 (s, 9H), 8.37
(d,
J=2Hz, 1H), 8.39 (t, J=211z, 1H), 8.80 (d, J=2Hz, 1H), 9.58 (brs, 1H); ESIMS
found
C10H13BrN20 m/z 257.0 (M+H).
89

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Br
0 LL,,
XXXI
[00360] N-(5-Bromopyridin-3-y1)-2-phenylacetamide (XXXI): White solid
(2.5 g, 8.59 mmol, 77.9% yield). ESIMS found C13H11BrN20 m/z 291 (M+H).
QyLBr
XV(II
[00361] N-(5-Bromopyridin-3-yl)benzamide (XXXII): White solid (2.7 g, 9.74
mmol, 60% yield). ESIMS found C12H9BrN20 m/z 277 (M+H).
0
XXXIII
[00362] N-(5-Bromopyridin-3-yl)cyclopropanecarboxamide (XXXIII): Off-
white solid, (83% yield), 1H NMR (CDC13, 500 MHz) 8 ppm 8.46-8.39 (m, 3H),
7.54
(bs, 1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found
for
C9H9BrN20 m/z 240.9 (M+H).
0
XXXIV
[00363] N-(5-Bromopyridin-3-yl)cyclobutanecarboxamide (X.XXIV): Yellow
solid (2.1 g, 6.27 mmol, 86.6% yield). ESIMS found C10Ht1BrI\120 m/z 255
(M+H).
QH
Br
0
XXXV

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[00364] N-(5-Bromopyridin-3-yl)cyclopentanecarboxamide (XXXV): Yellow
solid (1.9 g, 7.06 mmol, 80.2% yield). ESIMS found CI IHI3BrN20 m/z 269 (M+H).
0
XXXVI
[00365] N-(5-bromopyridin-3-yl)cyclohexanecarboxamide (XXXVI): Yellow
solid (2.0 g, 7.06 mmol, 84.3% yield). ESIMS found C121-115BrN20 m/z 283
(M+H).
XXXVII
[00366] N-(5-bromopyri din-3 -y1)-1-methylpip eridine-4-carboxamide
(XXXVH): Waxy brown solid, (43%, yield), 1H NMR (CDC13, 500 MHz) 6 ppm 1.67
(dq, 2H), 1.77 (d, 2H), 1.96 (t, 2H), 2.20 (s, 3H), 2.31 (m, 1H), 2.86 (d,
2H), 8.36 (s, 1H),
8.40 (s, 1H), 8.67 (s, 1H)m 10.34 (s, 1H); ESIMS found C12}116BrN30 m/z 297.8
(M13179+H) and 299.8 (mBr81+H)Br
0 0
XXXVIII
[00367] N-(5-brom opyri din-3 -yl)methan esulfon amide (XXXVIII): Off-white
solid, (67%, yield), 1H NMR (CDC13, 500 MHz) 6 ppm 3.14 (s, 3H), 7.80 (s, 1H),
8.40 (s,
1H), 8,41 (s, 1H), 10.28 (brs, 1H); ESIMS found C6H7BrN202S m/z 250.9
(M13r79+H) and
252.9 (Mrirsi+H).
OLBr
0 0
VOCIX
91

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[00368] N-(5-bromopyridin-3-yl)benzenesulfonamide (XXX1X): White solid,
(84%, yield), ill NMR (DMS0-016, 500 MHz) 6 ppm 7.58-7.61 (m, 2H), 7.65-7.67
(m,
2H), 7.83 (d, 2H), 8.15 (d, 111), 8.38 (d, 1H), 10.87 (brs, 1H); ESIMS found
C11119BrN202S m/z 314.3 (Mur8 444)
[00369] Preparation of intermediate (XLI) is depicted below in Scheme 7.
Or¨\NH
\ /
- I
CsCO3, Pd2(dba)3, xantphosN
dioxane, MW, 100 C, 3h
XL XLI
Scheme 7
Step 1
[00370] To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in
dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93
mmol)
and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding
Pd2(dba)3
(195 mg, 0.21 mmol). The reaction was microwaved at 90 C for 4 h. The reaction
was
poured into a mixture of CHC13/H20; the aqueous layer was separated, washed
with
water, then brine and concentrated under vacuum. The crude product was
purified on a
silica gel column (100% hexane 1:3
Et0Ac:hexatie) to give 4-(5-bromopyridin-3-
yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS
found
m/z 244 (1\4+H).
[00371] The following compound was prepared in accordance with the
procedure described in the above Scheme 7.
XLII
[00372] 1 -(5-
bromopyridin-3 -y1)-4-methylpiperazine (XLII): Brown oil (50%,
yield), IHNMR (DMSO-d6, 500 MHz) 6 ppm 2.21 (s, 311), 2.41-2.43 (m, 411), 3.22-
3.24
(m, 4H), 7.51-7.52 (m, 1H), 8.02 (d, J=1.9Hz, 1H), 8.28 (d, J=2.6Hz, 1H);
ESIMS found
Ci0Hl4BrN3 m/z 256 (114+H).
92

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[00373] Preparation of intet __ mediate 5-bromo-N,N-dimethylpyridin-3-amine
(XLIII) is depicted below in Scheme 8.
Me2N*HC1, K2CO3
DMF, 200 C, overnight
XL MIR
Scheme 8
Step 1
[00374] To a solution of 3,5-dibromopyridine (XL) (2.37 g, 10.0 mmol) in dry
DMF (20.0 mL) was added K2CO3 (4.5 g, 33 mmol) and dimethylamino hydrochloride
(1.79 g, 22 mmol). The mixture was heated overnight at 200 C in a sealed tube.
The
solution was cooled to room temperature and excess DMF was removed under
vacuum.
The residue was partitioned between Et0Ac and water. The organic phase was
separated. The aqueous phase was washed with Et0Ac and the combined organic
phases
were dried over MgSO4, and concentrated to afford 5-bromo-N,N-dimethylpyridin-
3-
amine (XLHI) as an off-white solid (1.78 g, 8.85 mmol, 88% yield). 1H NMR
(DMSO-
d6, 500 MHz) 8 ppm 2.94 (s, 6H), 7.25 (t, J=2Hz, 1H), 7.91 (d, J-2Hz, 1H),
8.07 (d,
J-2Hz, 1H); ESIMS found C7H9BrN2 m/z 201.1 (M H).
[00375] Preparation of intermediate 5-bromo-N-isopropylpyridin-3-amine
(XLIV) is depicted below in Scheme 9.
0
HOAc, NaCNBH3 Br
Me0H
XXII XLIV
Scheme 9
Steps 1
[00376] To a solution of 5-bromopyridin-3-amine (XXII) (535 mg, 3.09 mmol)
in Me0II (62 mL) was added acetone (296 L, 4.02 mL). The pH was adjusted to 4
using
HOAc and stirred for 30 min. NaCNBH3 (272 mg, 4.33 mmol) was added and stirred
at
room temperature overnight. The Me0H was removed under vacuum and the residue
was
93

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partitioned between Et0Ac and saturated aqueous NaHCO3. The organic layer was
dried
over MgSO4 and evaporated under vacuum. The crude product was purified on a
silica
gel column (100% hexane 90:10 hexane:E10Ac) to produce 5-bromo-N-
isopropylpyridin-3-amine (XLIV) as an oil which slowly solidified into an off-
white
solid (309 mg, 1.44 mmol, 47% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.12 (d,
J=6.3Hz, 6H), 3.55-3.59 (m, 1H), 6.03 (d, J=7.9Hz, 1H), 7.05-7.06 (m, 111),
7.75 (d,
J=2Hz, 1H), 7.90 (d, J=2Hz, 1H); ESIMS found CsII11BrN2 m/z 215 (M+H).
[00377] Preparation of intermediate 1-(5-bromopyridin-3-y1)-N,N-dimethyl
methanamine (XLVI) is depicted below in Scheme 10.
OHC,Br Br
Me2NH*HCI
NaBH(OAc)3
TEA, DCE
XLV XLVI
Scheme 10
Step 1
[00378] To a solution of 5-bromonicotinaldehyde (XLV) (5.0 g, 26.9 mmol) in
DCE (108 mL) was added climethylamine-HC1 (4.39 g, 53.8 mmol) and TEA (7.5 g,
53.8
mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc)3 was
added
and the reaction was stirred overnight at room temperature. The reaction was
diluted with
DCM and sat. aq. NaHCO3. The organic layer was separated, washed with water,
brine,
dried and concentrated under vacuum to produce 1-(5-bromopyridin-3-y1)-N,N-
dimethylmethanamine (XLVI) as a brown liquid (5.36 g, 24.9 mmol, 92.6% yield).
1H
NMR (CDC13) 8 ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=1.1Hz,
1H), 8.59
(d, J=2.2Hz, 1H); ESIMS found C81-111BrN2 m/z 215
(mBr79-Et) and 217 (Mrsi+H).
[00379] The following intermediates were prepared in accordance with the
procedure described in the above Scheme 10.
XL VII
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[00380] 3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XLVII): Golden liquid
(1.35 g, 97% yield). NIVIR (DMSO-d6) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H),
3.60 (s,
2H), 7.96 (s, 1H), 8.48 (d, J=2Hz. 1H), 8.58 (d, J=-3Hz, IH); ESIMS found for
C101113BrN2 m/z 242 (M+H).
XL VIII
[00381] 3 -Bromo-5-((3 ,3 -difluoropyrrolidin-1 -yl)methyl)pyridine (XLVIII):
Brown oil (6.4 g. 81% yield). ESIMS found for Ci0II11Br172N2 m/z 277.0 (M+H).
XLIX
[00382] 3-Bromo-5-(piperidin-1-ylmethyppyridine (XLIX): Brown liquid
(13.1 g, 94% yield). 1H NMR (DMSO-d6) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H),
2.31-
2.32 (m, 4H), 3.46 (s, 211), 7.94 (s, 111), 8.47 (d. J=2Hz, 1H), 8.58 (d,
J=3Hz, 1H);
ESTMS found for CI illi5BrN2 m/z 257 (M-1-11).
Br
[00383] N -((5-Bromopyridin-3-yl)methyl)ethanamine (L): Golden liquid (1.29
g, 6.00 mmol, 60% yield). ESIMS found for C5Ell1BrN2 mlz 215 (M+H).
H
LI
[00384] N-B enzyl-1 - (5 -bromopyri din-3 -yl)methanam ine (LI): Golden liquid
(77 mg, 0.28 mmol, 25% yield). ESIMS found for C13Hi3BrN2 inlz 277 (M+11).
[00385] Preparation of intettnediate tert-butyl (5-bromopyridin-3-yl)methyl
(cyclopentylmethyl)carbamate (LVI) is depicted below in Scheme 11.

CA 02853703 2014-04-25
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NH 0
OHC
NaBH4
Br
0
Me0H PPh3, DEAD
o
THF, 0- r. t.
XLV LII LIII
NH2NH2
Et0H
Sr r B IrD4)
CrY (Boc)20 H __ H2N
Boc Et3N, DCM NaBH3(CN)
Me0H
LVI LV LIV
Scheme 11
Step 1
[00386] To a solution of 5-bromonicotinaldehyde (XLV) (2.0 g, 10.8 mmol, 1
eq) in Me0H (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction
mixture was stirred at room temperature for 3 h. The mixture was concentrated
in vacuo
and the residue was diluted in water (15 mL), the aqueous phase was extracted
with DCM
(10 triL x 3). The combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LII) (1.8 g,
9.57 mmol,
90.0% yield) as a colorless oil. 111 NMR (CDC13, 500 MHz) 8 ppm 4.73 (s, 2H),
7.90 (s,
1H), 8,47 (s, 111), 8.57 (s, 1H). ESIMS found for C6H6BrNO in/z 188 (M+H).
Step 2
[00387] To a stirred solution of (5-bromopyridin-3-yl)methanol (LII) (1.60 g,
8.5 mmol, 1 eq), phthalimide (1.24 g, 8.5 mmol, 1 eq) and PPh3 (3.33 g, 12.75
mmol, 1.5
eq) in anhydrous THF (15 mL) was added DEAD (2.21 g, 12.75 mmol, 1.5 eq)
dropwise
at 0 C under N2. Then the reaction mixture was stirred at room temperature for
6 h. The
mixture was washed with saturated NaHCO3 solution (15 mL), water (15 mL) and
brine
(15 mL) subsequently. The organic layers were dried over MgSO4, concentrated
under
reduced pressure, the resultant residue was purified by flash chromatography
on silica gel
(PE:Et0Ac = 4:1) to give 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione
(LIII)
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(2.5 g, 7.88 mmol, 82.3% yield) as a white solid. ESIMS found for C14H9BrN202
m/ z 317
(M+H).
Step 3
[00388] A solution of 245-bromopyridin-3-yl)methy1)isoindoline-1,3-dione
(LHI) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in
Et0H (20
mL) was heated at 70 C for 3 h. The mixture was filtered through a Celite pad
and the
filtrate was concentrated in vacuo, the crude product was dissolved in 1N HC1
solution
(15 mL) and concentrated to dryness, then it was washed with acetone (10 mL x
3), the
precipitate was collected by filtration, dried in vacuo to give (5-
bromopyridin-3-
Amethanamine (LIV) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR
(D20,
500 MHz) 5 ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2Hz, HI), 8.91 (d,
J=1.6Hz,
1H). ESIMS found for C6H7BrN2 m/z 187 (M+H).
Step 4
[003891 A solution of (5-bromopyridin-3-yl)methanamine (LIV) (1.30 g, 5.8
mmol, 1.0 eq), cyclopentaneearbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA
(0.60 g,
5.8 mmol, 1.0 eq) in Me0H (15 mL) was stirred at room temperature for 2 h.
Then
NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at
the same
temperature for another 3 h. The solvent was removed under reduced pressure
and the
residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3),
combined
organic layers were dried over MgSO4 and concentrated in vacuo to give 145-
bromopyridin-3-y1)-N-(cyclopentylmethyl)methanamine (LV) (1.23 g, 4.57 mmol,
79.3%
yield) as a brown oil. ESIMS found for C12E117BrN2 m/z 269 (M+H).
Step 5
[00390] To a solution of 1-(5-bromopyridin-3-y1)-N-(cyclopentylmethyl)
methanamine (LV) (1.00 g, 3.7 mmol, 1 eq) and TEA (0.93 g, 9.2 mmol, 2.5 eq)
in DCM
(20 mL) was added portionwise (Boc)20 (0.85 g, 4.0 mmol, 1.1 eq) at 0 C, the
reaction
mixture was stirred at room temperature for 1 h. The mixture was washed with
water (10
mL), brine (10 mL), the organic layer was separated, dried over MgSO4 and
concentrated
97

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in vaeuo to give tert-butyl (5-bromopyridin-3-yl)methyl
(cyclopentylmethypcarbamate
(LVI) (1.25 g, 3.38 mmol, 91.9% yield) as a white solid. ESIMS found for
Ci7H25BrN202
m/z 369 (M+14).
1003911 Preparation of intermediate (LX) is depicted below in Scheme 12.
NH NH2 NH2
(H0)313
02NE3r 02N N
HOAc, Na0Ac 1,4-Dioxane, Na2CO3, 1120
Hr2, 100 C, 28 h Pd(PPh3)2Cl2, reflux., 15 h
LVI1 LVIII LIX
Me011, Pd/C-II2
rt, 15 h
NH2
I
N
LX
Scheme 12
Step 1
[00392] A mixture of 3-nitropyridin-4-amine (LVII) (10 g, 71.94 mmol) and
acetic acid (120 mL) was added to a sealed tube followed by addition of Na0Ac
(29.50g,
93.52mmo1) and dropwise addition of bromine (4.7m1 359.7 mmol) under stirring.
The
sealed tube was heated at 100 C for 28 h until TLC showed consumption of
starting
material. The reaction mixture was concentrated to obtain a solid which was
dissolved in
water, basified with NaHCO3 and extracted with Et0Ac. The combined organic
extracts
were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (LVIII)
as a
yellow solid (12 g, 55 mmol, 77% yield). 1H NMR (DMSO-d6) 6 ppm 9.19 ( s, 1H),
8.58
(s, 1H); ESIMS found for C5H4BrN302 m/z 217, 219 (M+, M+2).
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Step 2
[00393] A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (6 g, 26 mmol),
pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and
1,4-
dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2C12 (927 mg, 5
mmol%) was
added to the reaction and the solution was refluxed for 15h until TLC showed
the
reaction was complete. The reaction was passed through a pad of Celite and
then
concentrated under reduced pressure. The reaction mixture was concentrated and
the
residue was taken up in Et0Ac. The organic extract was washed with water,
dried and
concentrated under vacuum. The crude product was purified on a silica gel
column
(100% Et0Ac 2:98
MeOH:DCM) to give 5-nitro-3,3'-bipyridin-4-amine (LIX) as a
yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDC13, 500 MHz,) 6 ppm 9.31
( s,
1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H),7.52-
7.48 111).
ESIMS found CI0118N402 m/z 216.95 (M+H).
Step 3
[00394] To a solution of 5-nitro-3,3'-bipyridin-4-amine (LIX) (5 g, 23 mmol)
in Me0H (20 mL) was added 10% Pd/C. The solution was purged with hydrogen and
stirred at room temperature under hydrogen for 15 h. The suspension was
filtered through
Celite and the concentrated under vacuum to produce 3,3'-bipyridine-4,5-
diamine (LX)
as off white solid (3.3 g, 17.7 narnol, 76% yield). 1H NMR (DMSO-d6, 500
MHz,): 6
ppm 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.48-
7.43 (m, 2H),
6.13 (bs, 2H), 5.31 (bs, 211). ESIMS found CieHi0N4 m/z. 187.10 (M+H).
[00395] The following compounds were prepared in accordance with the
procedure described in the above Scheme 12.
NH2 N
LXI
[00396] 3,4'-Bipyridine-4,5-diamine (LXI): Light tan solid, (84% yield).
ESIMS found C10Hi0N4 trilz 187.0 (M+H).
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NH2
LXII
[00397] 2,3'-Bipyridine-4',5'-diamine (LXII): Tan amorphous solid, (76%
yield). ESIMS found C10H10N4m/z 187.0 (M+H).
NH2
H2N =N
JIIIL
LXIII
1003981 5-(3-Fluorophenyl)pyridine-3,4-diamine (LXIII): Off white solid,
(76% yield), 1H NMR (CDC13, 500 MHz) 8 ppm 4.72 (s, 211), 5.07 (s, 2H), 7.17-
7.23 (m,
3H), 7.44 (s, 11-1), 7.48-7.52 (m, 111), 7.68 (s, 1H); ESIMS found C111-110FN3
m/z 204.1
(M+H).
NH2
H2N
JZIIIi
LXIV
[00399] 5-(4-Fluorophenyl)pyridine-3,4-diamine (LXIV): Light yellow solid,
(97% yield). ESIMS found C111-110FN3 m/z 204.3 (M+H).
NH2
H2N
F
LXV
[00400] 5-(2-Fluorophenyl)pyridine-3,4-diamine (LXV): Light red solid, (44%
yield). ESIMS found CI ithoEN3 m/z 204.4 (M+H).
NH2
H2N F
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LXVI
[00401] 5'-Fluoro-3,31-bipyridine-4,5-diamine (LXVI): Off white solid, (100%
yield), 1I-1 NMR (CDCI3, 500 MHz) 6 ppm 4.78 (s, 2H), 5.28 (s, 2H), 7.46 (s,
1H), 7.70
(s, 1H), 7.73-7.76 (m, 1H), 8.44-8.45 (m, 111), 8.56 (d, J=2.8Hz, 1H); ESIMS
found
Ci0H9EN4 m/z 205 (M+H).
NH, o
H2N r
LXVII
[00402] 5-(Furan-3-yl)pyridine-3,4-diamine (LXVII): Light pink solid, (68%
yield). ESIMS found C9H9N30 tnlz 176.0 (M+H).
NH, rs
H2 N I /
LXVIII
[00403] 5-(Thiophen-3-yl)pyridine-3,4-diamine (LXVIII): Light brown
amorphous solid, (100% yield). ESIMS found C9H9N3S m/z 192.0 (M--H).
NH2
H2N s
LMX
[00404] 5-(thiophen-2-yl)pyridine-3,4-diamine (LXIX): White amorphous
solid, (1.257 g, 6.57 mmol, 100% yield). ESIMS found C9H9N3S m/z 192.2 (M+H).
[00405] Preparation of intermediate (LXXI) is depicted below in Scheme 13.
NH2 NH2 NH2
\NH 02N H2N
140 C Me0H, Pd/C-H2
rt, 15 h
LVIII LXX LXXI
Scheme 13
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Step 1
[00406] A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (618 mg, 2.83
mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140 C overnight.
The
reaction was poured into an Et0Ac/H20 mixture; the organic layer was
separated, dried
over MgSO4 and concentrated under vacuum. The crude product was purified on a
silica
gel column (100% CHC13 ---> 3:97 Me0H(7N NH3):CHC13) to give 3-(4-
methylpiperazin-
l-y1)-5-nitropyridin-4-amine (LXX) as a yellow solid (382 mg, 1.61 mmol, 56.7%
yield).
1H NMR (CDC13, 500 MHz,) 8 ppm 2.20 (s, 311), 2.35-2.37 (m, 4H), 4.52-3.54 (m,
4H),
5.96 (s, 1H), 7.42 (s, 211), 8.78 (s, 1H); ESIMS found C101115N502 m/z 238
(M+H).
Step 2
[00407] To a solution of 3-(4-methylpiperazin-1-y1)-5-nitropyridin-4-amine
(LXX) (382 mg, 1.61 mmol) in Me0H (11 mL) was added 10% Pd/C. The solution was
purged with hydrogen and stirred at room temperature under hydrogen for 4 h.
The
suspension was filtered through Celite and the concentrated under vacuum to
produce 5-
(4-methylpiperazin-1 -yl)pyridine-3,4-diamine (LXXI) as purple solid (330 mg,
1.59
mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz,): 8 2.18 (s, 3H), 2.34-2.36 (m,
4H),
3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H);
ESIMS found
C10Hi7N5 m/z 208 (M+H).
[00408] The following compounds were prepared in accordance with the
procedure described in the above Scheme 13.
NH2
LXXII
[00409] 5-Morpholinopyridine-3,4-diamine (LXXII): 1H NMR (DMSO-d6,
500 MHz) ö ppm 3.10 (t, 4H), 3.65 (t, 4H), 3.93 (brs, 2H), 5.23 (brs, 211),
5.94 (s, 111),
7.33 (s, 111); ESIMS found C91114N40 m/z 195 (M+H).
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NH2
LXXIII
[00410] 5-(Piperidin-1-yl)pyridine-3,4-diamine (LXXIII): Purple solid, (83%
yield). ESIMS found C10H16N4 m/z 193.1 (M+H).
[00411] Preparation of intermediate (LXXVIII) is depicted below in Scheme
14.
Br HN >-ck 07 HN
8-8
BrF tBuOK BrF KOAe, PdC12(dP1)02 0- B
toluene, 110 C DMF, 95 C, 2 h 0
LXXIV LXXV LXXVI
NH2
02N Br
NI
LVIII
K3PO4, Pd(PPh3)4
HN
10% Pd/C-H2 1120, 100 C, 3 h
NH2 NH2
H2N 02N
Me0H
LXXVIII LXXVII
Scheme 14
Step 1
[00412] To a solution of 1,3-dibromo-5-fluorobenzene (LX,XIV) (4 g, 15.75
mmol) in toluene (50 mL) was added li3u0K (5.3 g, 47.25 mmol) and Ni,N1,N2-
trimethylethane-1,2-diamine (2.778 mL, 31.5 mmol). The reaction was stirred at
110 C
overnight. The solvent was removed under vacuum and the residue was
partitioned
between Et0Ac and water. The organic layer was separated, washed with water,
brine,
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dried over MgSO4 and evaporated under vacuum. The crude product was purified
on a
silica gel column (100% CHC13 ---> 5:95 MeOH:CHC13) to produce N1-(3-bromo-5-
fluoropheny1)-N2,N2-dimethylethane-1,2-diamine (LXXV) as a brown viscous oil
(1.02
g, 3.91 mmol, 24.8% yield). 1H NMR (DMSO-d6, 500 MHz) 8 ppm 2.17 (s, 6H), 2.40
(t,
J=3.5Hz, 2H), 3.01-3.09 (m, 2H), 6.10 (t, J=514z, 114), 6.38 (dt, J=12Hz,
J=2Hz, 1H),
6.51 (dt, J=8.5Hz, HI), 6.60
(s, 1H); ESIMS found C121-116BrEN2 inlz 261 (M+H).
Step 2-3
[00413] A solution of N1-(3-bromo-5-fluoropheny1)-N2,N2-dimethylethane-1,2-
diamine (LXXV) (5 g, 19.15 mmol), bis(pinacolato)diboron (5.83 g, 22.98 mmol),
KOAc
(5.63 g, 57.45 mmol) and dry DMF (20 mL) was purged with argon. PdC12(dppf)2
(938
mg, 1.15 mmol) was added to the reaction and purged again with argon. The
solution was
heated at 95 C for 2 h. Once TLC showed the disappearance of (LXXV), the
solution
was cooled to room temperature. To this solution was added K3PO4 (6.09 g,
28.72
mmol), 3-bromo-5-nitropyridin-4-amine (LVIII) (4.17 g, 19.15 mmol), Pd(PPh3)4
(663
mg, 0.57 mmol) and water (4 mL). The solution was purged with argon and heated
at
100 C for 4 h. The solution was cooled to room temperature and then
concentrated under
reduced pressure. The residue was partitioned between DCM and water. The
aqueous
phase was filtered through Celite and concentrated under vacuum. The residue
was
purified on a silica gel column (100% CHC13 5:95
MeOH:CHC13) to give N1-(3-(4-
amino-5 -nitropyridin-3 -y1)-5 -fiuoropheny1)-N2,N2-dimethylethane-1,2-diamine
(LXXVI1) as a yellow amorphous solid (3.30 g, 10.33 mmol, 54.0% yield for 2
steps). 1H
NMR (DMSO-d6, 500 MHz) 8 ppm 2.18 (s, 6H), 2.44 (t, J=6.5Hz, 2H), 3.12 (q,
J=6Hz,
2H), 6.01 (t, J=5Hz, 1H), 6.35 (d, J---9Hz, 1H), 6.43 (s, 1H), 6.48 (dt,
J=10Hz, J=2Hz,
1H), 7.32 (brs, 2H), 8.10 (s, 11-1), 9.01 (s, 1H); ESIMS found for C15HON502
m/z 320.3
(M+H).
Step 4
[00414] To a solution of N1-(3-(4-amino-5-nitropyridin-3-y1)-5-fluoropheny1)-
N2,N2-dimethylethane-1,2-diamine (LXXVII) (2.1 g, 6.58 mmol) in Me0H (40 mL)
was
added 10% Pd/C (300 mg, 15% by wt). The solution was purged with hydrogen and
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stirred for 4 h at room temperature under hydrogen. The suspension was
filtered through
Celite and concentrated under vacuum to produce 5-(3-(2-
(dimethylamino)ethylamino)-
5-fluorophenyl)pyridine-3,4-diamine (LXXVIII) as a brown solid (1.90 g, 6.57
mmol,
99.8% yield). 11-I NMR (DMSO-d6, 500 MHz) 6 ppm 2.20 (s, 6H), 2.46 (t, J=7Hz,
2H),
3.12 (q, J=6Hz, 21-1), 4.79 (s, 2H), 5.21 (s, 21-1), 5.91 (t, .P.--5Hz, 1H),
6.28 (dd, J=9Hz,
111), 6.36 (t, J=2Hz, 1H), 6.37-6.42 (m, 1H), 7.46 (s, 1H), 7.64 (s, 1H);
ESIMS
found C15H20FN5 m/z 290.1 (M+H).
[00415] Preparation of intermediate (LXXXHI) is depicted below in Scheme
15.
0 0
0J e I
NH NH
CHO
H2N¨S02CH3 Z1ç-o1 N
Br
NaBH(OAc)3, TEA KOAc, PdC12001)02 0,B Br
DCE DMF, 90 C, 2 h
LXXIX LXXX o LXXXI
NH2
0 0 LVITI I
H K3PO4, Pd(PP113)4
NHN
H20, 90 C, 3 h
NH2 NH2
H2N F 10% Pd/C-H2
Me011
N
LXXXIll LXXXII
Scheme 15
Step 1
[00416] To a solution of 3-bromo-5-fluorobenzaldehyde (LX.XIX) (2.03 g,
10.01 mmol) in DCE (50 mL) was added methanesulfonamide (1.43 g, 15.01 mmol)
and
TEA (2.79 mL, 20.02 mmol). NaBH(OAc)3 (3.00 g, 14.13 mmol) was added and
stirred
at room temperature overnight. The solvent was removed under vacuum and the
residue
was partitioned between Et0Ac and water. The organic layer sparated and washed
with
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water, brine, dried over MgSO4 and evaporated under vacuum to produce N-(3-
bromo-5-
fluorobenzypmethanesulfonamide (LXXX) as a colorless oil (2.653 g, 9.40 mmol,
93.9%
yield). ESIMS found C8H9BrFNO2S nilz 282.0 (M+H).
Step 2-4
[00417] Procedures can be found in Scheme 13, Steps 2-4. N-(3-(4,5-
Diaminopyridin-3-y1)-5-fluorobenzyl)methanesulfonamide LXXXIII was isolated as
a
light tan solid (428.4 mg, 1.38 mmol, quantitative yield). 114 NMR (DMSO-d6,
500 MHz)
8 ppm 2.92 (s, 3H), 4.24 (d, J=6.311z, 21-I), 4.80 (s, 211), 5.23 (s, 2H),
7.11-7.13 (m, 1H),
7.16-7.18 (m, 1H), 7.22 (s, 1H), 7.47 (s, 1H), 7.64 (d, J=6.3Hz, 1H), 7.68 (s,
1H); ESIMS
found C13H15FN402S mlz 311 (M+H).
Example 1.
[00418] Preparation of compound (1) is depicted below in Scheme 16.
0NH
H H Bryl-Ny-y
0 I,- I
N
N KOAe, Pda2OPPO2 K2PO4, Pd(PPb3)4
DMF, 80 C, 2 h DMF, 1120,90 C, 3 h
III ob
LXXX1V
NE12
ji DMF, suifu
r
140 C, ON
LXXI
TIXI
N\ NH \ NH
N
\N Et3SiH, DCM
TFA, r.t, 2
LXXXV 03
Scheme 16
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Step 1-2
[00419] A solution of 5 -io do-1-(tetrahydro-2H-pyran-2-y1)-1H-indazole-3-
carbaldehyde (II) (498 mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6
mmol),
KOAc (412 mg, 4.2 mmol) and dry DMF (10 mL) was purged with nitrogen.
Pd(dPPD2C12 (68 mg, 0.08 mmol) was added to the reaction and purged again with
nitrogen. The solution was heated at 90 C for 2 h. Once TLC showed the
disappearance
of (II), the solution was cooled to room temperature. To this solution was
added K3F04
(446 mg, 2.1 mmol), N-(5-bromopyridin-3-y1)-3-methylbutanamide (XXVIII) (358
mg,
1.4 mmol), Pd(PPh3)4 (48 mg, 0.042 mmol) and water (2 mL). The solution was
purged
with nitrogen and heated at 90 C for 4 h. The reaction was passed through a
pad of
Celite and then concentrated under reduced pressure. The residue was
suspended in
water, sonicated, filtered and dried. The crude product was purified on a
silica gel column
(100% DCM .. 3:97 MeOH:DCM) to give N-(5-(3-formy1-1-(tetrahydro-2H-pyran-2-
y1)-1H-indazol-5-yl)pyridin-3-y1)-3-methylbutanamide (LXXXIV) as an off white
solid
(239 mg, 0.59 mmol, 42% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 0.96 (d, 611),
1.60-1.67 (m, 1H), 1.75-1.84 (m, 1H), 2.05-2.15 (m, 3H), 2.26 (d, 2H), 2.39-
2.47 (m,
1H), 3.80-3.86 (m, 1H), 3.89-3.93 (m, 114), 6.13 (dd, 1H), 7.91 (dd, 1H), 8.06
(d, 1H),
8.36 (s, 1H), 8.39 (s, 1H), 8.63 (d, 1H), 8.81 (d, 1H), 10.23 (s, 1H); ESIMS
found
C2311261\1403 mtz 407.3 (M+H).
Step 3-4
[00420] A solution of N-(5-(3-formy1-1-(tetrahydro-2H-pyran-2-y1)-111-
indazol-5-yl)pyridin-3-y1)-3-methylbutanamide (LXXXIV) (52 mg, 0.127 mmol),
544-
methylpiperazin-1 -yl)pyridine-3,4-diamine (LVIII) (29 mg, 0.13 mmol) and
sulfur (45
mg, 0.13 mmol) in dry DMF (10 mL) was heated at 140 C overnight. The reaction
was
cooled and evaporated under vacuum. The viscous residue was dried overnight
under
vacuum. The solid was washed with cold water and dried under vacuum. The crude
product (LXXXV) was dissolved in DCM (5 mL) followed by Et3SiH (48 L, 0.30
mmol) and slowly addition of TFA (2.5 mL). The reaction was stirred until TLC
(10%
Me0H/DCM) showed the reaction was complete. The reaction was evaporated under
vacuum and the residue was treated with water, sonicated and then basified
with aq.
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ammonia. The solids were filtered, washed with cold water and dried. The crude
product
was heated in Et0Ac and filtered hot to remove impurities. The hot Et0Ac
solution was
allowed to slowly cool to room temperature and filtered to give 3-methyl-N-(5-
(3-(7-(4-
methylpiperazin-l-y1)-311-imidazo [4,5-c]pyridin-2-y1)-1H-indazol-5-yepyridin-
3-
yl)butanamide 1 as a pink solid (36 mg, 0.071 mmol, 59% yield). 111 NMR (DMSO-
d6,
500 MHz) 6 ppm 0.97 (d, 6H), 2.13 (m, 1H), 2.27 (m, 411), 3.45 (m, 4H), 6.70
(s, 1H),
7.79 (dd, 2H), 8.36 (s, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 8.66 (s, 1H), 8.84
(s, 111), 10.26 (s,
1H), 12.97 (s, 1H), 13.82 (s, 1H); ESIMS found for C28H31N90 m/z 510.5 (M+H).
[00421] The following compounds were prepared in accordance with the
procedure described in the above Example 1.
/
CeNH
\ NH
N
\ N
14/
2
[00422] N-(5-(3-(7-(4-methylpiperazin-1 -y1)-311-imidazo [4,5-c]pyridin-2 -y1)-
1H-indazol-5-yOpyridin-3-yHisobutyramide 2
[00423] Brick red solid (35% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm
1.16 (d, 6H), 2.33 (brs, 311), 2.58 (m, 4H), 2.64 (m, 111), 3.49 (m, 411),
6.71 (s, 111), 7.79
(dd, 2H), 8.38 (s, 1H), 8.62 (s, 111), 8.66 (s, 2H), 8.86 (dd, 1H), 10.23 (s,
111), 12.99 (s,
1H), 13.83 (s, 1H); ESIMS found for C27H29N90 m/z 496.4 (M+H).
N
3
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[00424] N,N-dimethy1-1 -(5 -(3-(7-(4-methylpiperazin-1 -y1)-3H- imidazo [4,5-
e]pyridin-2-y1)-1H-indazol-5 -yl)pyri din-3 -yl)methanamine 3
[00425] Off white solid (63% yield). 111 NMR (DMSO-d6, 500 MHz) 43 PPm
2.22 (s, 6H), 2.24 (s, 3H), 2.46 (m, 4H), 3.45 (m, 4H), 3.55 (s, 2H), 6.69 (s,
1H), 7.81
(dd, 21-0, 8.03 (s, 1H), 8.51 (d, 1I1), 8.65 (s, 1H), 8.68 (s, 1H), 8.84 (d,
1H), 12.95 (brs,
1H), 13.81 (brs, 1H); ESIMS found for C26H29N9 M/Z 468.3(M+H).
fq/Th
/ N\I
N \ NH
N
\N
4
[00426] 7-(4-
methylpiperazin-1-y1)-2-(5-(pyridin-3-y1)-1H-indazol-3-y1)-3H-
imidazo[4,5-c]pyridine 4
[00427] Light brown solid (51% yield). 1H NMR (DMSO-do, 500 MHz) &
ppm 2.24 (s, 3H), 2.56-2.67 (m, 4H), 3.43-3.54 (m, 4H), 6.72 (s, 1H), 7.55
(dd, 1H), 7.83
(dd, 2H), 8.16 (dd, 1H), 8.61 (dd, 1H), 8.66 (s, 1H), 8.70 (s, 1H), 8.96 (d,
1H), 13.00 (brs,
1H), 13.82 (s, 1H); ESIMS found C23H22N8 M/Z 411.1 (M+H).
ON
N I
\ NH
NI
\N
NI
[00428] 44543 -(7-(4-methylpiperazin-1-y1)-3 H-imidazo [4 ,5-c]pyri din-2-y1)-
1H-indazol-5-yl)pyridin-3 -yl)morpholine 5
[00429] Off white solid (69% yield). 1H NMR (DMSO-d6, 500 MHz) 6 PPm
2.24 (s, 3H), 2.46 (m, 4H), 3.36 (m, 4H), 3.45 (m, 4I1), 3.80 (t, 411), 6.69
(s, 1H), 7.57 (s,
1H), 7.80 (dd, 2H), 8.35 (dd, 2H), 8.66 (d, 1H), 12.92 (brs, 1H), 13.76 (brs,
1H); ESIMS
found C27H29N90 m/z 4.96.5 (M+H).
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07Th
Z N\1
N \ NH
N
6
[00430] 4-(2-(5-
(pyridin-3-y1)-1H-indazol-3-y1)-3H-imidazo[4,5-e[pyridin-7-
yl)morpholine 6
[00431] Beige solid (65% yield). 111 NMR (DMSO-d6, 500 MHz) 6 ppm 3.41
(t, 4H), 3.76 (t, 4H), 6.75 (brs, 1H), 7.56 (dd, 1H), 7.83 (dd, 2H), 8.17 (dd,
1H). 8.62 (d,
1H), 8.66 (brs, 1H), 8.71 (s, 1H), 8.96 (s, 1H), 13.05 (brs, 1H), 13.84 (s,
1H); ESIMS
found C221-119N70 mtz 398.0 (M+H).
/N
N.)
N\ NH
7
[00432] 2-(5-(5-(4-methylpiperazin-l-yppyridin-3-y1)-1H-indazol-3-y1)-3H-
imidazo[4,5-c[pyridine 7
[00433] Off white solid (68% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm
2.29 (s, 3H), 2.57 (m, 4H), 3.35 (m, 4H), 7.52 (brs, 1H), 7.57 (1, 1H), 7.81
(dd, 2H), 8.34
(m, 3H), 8.70 (s, 1H), 9.06 (brs, 11-0, 13.45 (brs, IH), 13.89 (brs, 1H);
ESIMS found
C23H22N8 M/Z 410.9 (M+11).
/ N
e-"NH
N\ NH
\N
9
110

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[00434] N-(5-(3-(31-1-imidazo[4,5-c]pyridin-2-y1)-1H-indazol-5-yl)pyridin-3-
y1)isobutyramide 9
[00435] Tan solid (63% yield). 111 NMR (DMSO-d6, 500 MHz) 6 ppm 1.16 (d,
611), 2.67 (sep, HI), 7.53 (d, 1H). 7.79 (dd, 211), 8.34 (d, 111), 8.40, (s,
1H), 8.63 (d, 1H),
8.70 (s, 111), 8.87 (s, 1H), 9.06 (s, 1H), 10.27 (s, 1H), 13.49 (s, 1H), 13.98
(s, 111);
ESIMS found C221119N70 7121z 3.98.0 (M+1-1).
/ N
0NH
N\ NH
\N
[00436] N-(5-(3-(7-(3-fluoropheny1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-
indazol-5-yOpyridin-3-y1)-3-methylbutanamide 10
[00437] White solid (98% yield). 111 NMR (DMSO-d6, 500 MHz) 6 ppm 0.98
(d, 611), 2.13 (m, 1H), 2.28 (d, 211), 7.24 (t, 111), 7.60 (dd, 1H), 7.84 (dd,
2H), 8.27 (d,
111), 8.38 (d, 111), 8.49 (s, 1H), 8.66 (s, 111), 8.77 (s, 2H), 8.87 (d, 2H),
10.23 (s, 111),
13.81 (brs, 1H), 14.05 (s, 111); ESIMS found C29H24FN70 rn/z 506.1(M+H).
/ N
0NH
N\ NH
\N
11
[004381 N-(5-(3-(7-(2-fluoropheny1)-3H-imidazo[4,5-c]pyridin-2-y1)-111-
indazol-5-y1)pyridin-3-y1)-3-methylbutanamide 11
[004391 White solid (37% yield). 1-11 NMR (DMSO-d6, 500 MHz) 8 ppm 0.98
(d, 6H), 2.13 (m, 1H), 2.29 (d, 2H), 7.37-7.41 (m, 2H), 7.48-7.63 (m, 111),
7.77-7.84 (m,
2H), 8.15 (m, 1H), 8.30-8.45 (m, 1H), 8.51-8.60 (dd, 111), 8.73 (dd, 1H), 8.85
(m, 2H),
111

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8.88 (s, 1H), 10.27 (m, 1H), 13.68 (brs, 1H), 14.93 (s, 1H); ESIMS found
C29H24FN70
m/z 506.3(M+H).
F
N\ NH
N
\ N
12
[00440] N-(5-(3-(7-(4-fluoropheny1)-3H-imidazo[4,5-e]pyridin-2-y1)-1H-
indazol-5-yOpyridin-3-y1)-3-methylbutanamide 12
[004411 White solid (50% yield). 1H NMR (DMSO-d6, 500 MHz) 8 ppm 0.98
(d, 6H), 2.17 (m, 1H), 2.32 (d, 2H), 7.40 (m, 2H), 7.84 (s, 2H), 8.45 (m, 2H),
8.58 (s,
1H), 8.67 (s, 211), 8.72 (d, 1H), 8.83 (m, 2H), 10.30 (s, 1H), 13.71 (brs,
1H), 14.02 (s,
1H); ESIMS found C29H24FN70 m/z 506.1(M+H).
N
N\ NH
NI
\N
[004421 7-(3-fluoropheny1)-2-(5-(pyridin-3-y1)-1H-indazol-3-y1)-3H-
imidazo[4,5-c]pyridine 15
[00443] Brown solid (75% yield). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 7.32
(td, 1H), 7.65 (m, 1H), 7.61 (dd, 1H), 7.85 d, 11I), 7.92 (d, 1H), 8.20 (d,
2H), 8.49 (d,
1H), 8.63 (dd, 1H), 8.78 (s, 1H), 8.88 (s, 1H), 8.94 (s, 1H), 9.03 (1H), 13.82
(brs, 1H),
14.02 (s, 1H); ESIMS found C241115FN6 m/z 407.3 (M+H).
112

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N
N--
N \ NH
N
\N
16
[00444] 1-(5-(3-(7-(5-fluoropyridin-3-y1)-3H-imidazo[4,5-c]pyridin-2-
y1)-1H-
indazol-5-yl)pyridin-3-y1)-N,N-dimethylmethanamine 16
[00445] Off white solid (60% yield). Ili NMR (DMSO-d6, 500 MHz) 6 PPm
2.36 (brs, 611), 3.69 (brs, 2H), 7.85 (d, 1H), 7.91 (d, 1H), 8.07 (s, 1H),
8.56 (s, 111), 8.67
(d, HI), 8.83 (m, 311), 8.92 (s, 2H), 9.49 (s, 1H), 13.86 (s, tH), 14.06 (s,
HI); ES1MS
found C26H21FN8 )17/2. 465.0 (M+H).
/ N
N--
0NH
N
\ NH
N
[00446] N-(5-(3-(7-(5-fluoropyridin-3-y1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3-yl)propionamide 20
100447] Brown solid (63% yield). 1H NMR (DMSO-d6, 500 MHz) 5 ppm 1.13
(t, 3H), 2.41 (m, 2H), 7.81-7.87 (m, 2H), 8.45 (s, 1H), 8.65 (s, 211), 8.78-
8.93 (m, 4H),
9.40 (s, Hi), 10.20 (s, 1H), 13.91 (brs, 1H), 14.02 (s, 1H); ESIMS found
C261119FN80 m/z
479.1(M+H).
113

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N
0`===NH
N\ NH
\N
Hi
24
[00448] N-(5-(3 -(7(3 -Fluoropheny1)-311-imidazo [4,5-c]pyridin-2 -y1)-1H-
indazol-5-yl)pyridin-3 -yl)propionamide 24
[00449] Tan solid (37.5 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.14 (t,
j=7.51-1z, 311), 2.44 (q, J=7.5Hz, 2H), 7.28 (t, J-8Hz, 1H), 7.61 (q, J=8Hz,
1H), 7.84 (q,
J-8.5Hz, 2H), 8.23 (brs, 1H), 8.35 (brs, 1H), 8.50 (s, 111), 8.67 (s, 1H),
8.76 (s, 2H), 8.85
(s, 111), 8.93 (brs, 111), 10.24 (s, 111), 14.07 (s, 1H); ESIMS found
C27H20FN70 m/z 478.3
(M+H).
0.'NNH
N \ NH
NI
,N
31
[00450] N-(5-(3-(7-(2-Fluoropheny1)-3H-imidazo [4,5-c]pyridin-2-y1)-1H-
indazol-5-yppyridin-3-yl)isobutyramide 31
[00451] Beige solid (27.5 mg, 20.3% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.17 (d, J=6.5Hz, 6H), 2.68 (sex,J=7Hz, 1H), 7.40-7.52 (m, 3H), 7.55-7.63
(m, 2H),
7.84 (dd, J=9Hz, J=1.5Hz, 1H), 7.90 (d, J=8.5Hz, 111), 8.50 (brs, 1H), 8.62
(s, 1H), 8.72
(s, 2H), 8.80 (brs, I H), 10.27 (s, 111), 13.09 (brs, 1H), 14.29 (brs, 1H);
ESIMS found
C28}122FN70 m/z 492.2 (M+1-1).
114

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0 NH
N\ NH
Ni
/1 4
86
[00452] N-(5 -(3 -(743 -Fluoropheny1)-3 H-imidazo [4,5-c] pyridin-2-y1)-1H-
indazol-5 -yl)pyridin-3 -y1)-2-ph enylacetamide 86
[00453] Beige solid (14.1 mg, 16.1% yield). 11-INMR. (DMSO-d6, 500 MHz) 5
ppm 3.76 (s, 2H), 7.18 (t, J=6.5Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 7.29-7.42 (m,
4H), 7.81
(d, J=7.5Hz, 1H), 7.85 (d, J=8.5Hz, 1H), 8.25 (d, J=7.5Hz, 111), 8.36 (d,
J=11Hz, 1H),
8.50 (s, 1H), 8.66 (s, 1H), 8.76 (s, 1H), 8.77 (s, 1H), 8.86 (d, J=3Hz, 1H),
10.56 (s, 1H),
13.77 (s, 1H), 14.04 (s, 1H); ESIMS found C321-122FN70 nilz 540.5 (M+H).
/N
N\ NH
N
I N
89
[00454] 1-(5-(3 -(7-(3-Fluoropheny1)-3H-imidazo [4,5-c]pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3-y1)-N,N-dimethylmethanamine 89
[00455] Light brown solid (16.1 mg, 19.0% yield). 1H NMR (DMSO-d6, 500
MHz) 6 ppm 2.30 (brs, 9H), 3.69 (brs, 2H), 7.31 (dt, J=2.5Hz, J=8.5Hz, 111),
7.61 (q,
.J=7.5Hz, 1H), 7.85 (d, J=9Hz, 1H), 7.91 (d, J-9Hz, 1H), 8.08 (brs, 1H), 8.23
(d,
J=7.5Hz, 1H), 8.32 (d, J=7Hz, 1H), 8.40 (s, 1H), 8.76 (s, 1H), 8.88 (d, J=7
.5Hz, 2H),
8.99 (s, 1H), 13.78 (brs, 1H), 14.04 (brs, 1H); ESIMS found C27H22FN7 nilz
463.9
(M+H).
115

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N
0 NH
N\ NH
N
I-1
[00456] N-(5-(3 -(743 -FluorophenyI)-3 H-imidazo [4,5-eipyridin-2-y1)-111-
indazol-5-yl)pyridin-3 -y1)-3 ,3-dimethylbutanamide 90
[00457] Light brown solid (10.5 mg, 5.9% yield). 11-I NMR (DMSO-d6, 500
MHz,) 6 ppm 1.06 (s, 9H), 2.28 (s, 2H), 7.24 (dt, J=8.511z, J=2Hz, 1H), 7.59
(q, J=8Hz,
1H), 7.81 (d, J=8.5Hz, 1H), 7.86 (d, J=8,5Hz, 1H), 8.26 (d, J=8Hz, 1H), 8.38
(d, J=11Hz,
1H), 8.49 (s, 1H), 8.66 (d, J=1.5Hz, 1H), 8.77 (dd, J=5.5Hz, J=2Hz, 2H), 8.87
(d, J=8Hz,
2H), 10.17 (s, 1H), 13.78 (s, 1H), 14.04 (s, 1H); ESIMS found C30H26FN70 adz
520.3
(M-1-1).
01.
NH N
N
91
[00458] N-(5 -(3 -(7-(3 -Fluoropheny1)-311-imidazo [4,5-c] pyridin-2 -y1)-1H-
indazol-5 -yl)pyridin-3 -yl)cyclopropaneearbox amid e 91
[00459] Yellow white solid (3.7 mg, 1.5% yield). 111 NMR (DMSO-d6, 500
MHz) 6 ppm 0.92-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.86 (quin, J=4.5Hz, 1H),
7.18 (dt,
J=8Hz, J=2Hz, 1H), 7.56 (q, J=--8Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.76 (dd,
J=8.5Hz,
J=1.5Hz, 1H), 7.86-8.10 (m, 2H), 8.47 (t, J=2.5Hz, 1H), 8.50 (brs, 1H), 8.62
(d, J=2Hz,
1H), 8.74 (d, J=2.51-Iz, 1H), 8.82 (s, 2H); ESIMS found C281-120FN70 mlz 489.8
(MH-H).
116

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0 F
ONH
N )NH
N
94
[004601 N-(5-(3-(7-(3-Fluoropheny1)-3H-imidazo[4,5-e]pyridin-2-y1)-1H-
indazol-5-yOpyridin-3-yl)cyclohexanecarboxamide 94
[00461] Light brown solid (27.6 mg, 29.0% yield). 111 NMR (DMSO-d6, 500
MHz) 6 ppm 1.16-1.25 (m, 1H), 1.31 (q, J=12.5Hz, 2H), 1.45 (q, J=12Hz, 211),
1.67 (d,
J=11.5Hz, 1H). 1.79 (d, J-12.5Hz, 2H), 1.88 (d, J=12Hz, 211), 2.41 (dq, J=8Hz,
Hi), 7.22 (dt, J=8Hz, J=2Hz, 1H), 7.60 (q, J=7.5Hz, 1H), 7.84 (q, J=9Hz, 2H),
8.28 (d,
8Hz, 1H), 8.39 (t, J=11Hz, 1H), 8.51 (s, 111), 8.66 (d, J-1.5Hz, 1H). 8.77 (s.
2H), 8.86
(d, J=6Hz, 211), 10.17 (s, 1H), 13.77 (s, 1H), 14.04 (s, 1H); ESIMS found
C311126FN70
nilz 532.2 (M+H).
NH2
N
\ NH
N
\ N
isr
97
[00462] 5-(3-(7-(4-Fluoropheny1)-3H-imidazo[4,5-c]pyridin-2-y1)-114-
indazol-
5-Apyridin-3-amine 97
[004631 Tan solid (51.0 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 5.53 (brs,
211), 7.31-7.42 (m, 3H), 7.78 (q, J=8Hz, 114), 7.99 (d, J=2Hz, 1H), 8.16 (s,
1H), 8.23
(brs, 1H), 8.46 (brs, 211), 8.67 (s, 1H), 8.84 (s, 2H), 13.72 (brs, 111),
14.02 (brs, 1H);
ESIMS found C241-116171\17mtz 422.0 (M+H).
117

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N
\ NH
\N
99
[004641 7-(4-Fluoropheny1)-2-(5-(4-methylpyridin-3-y1)-1H-indazol-3-y1)-3H-
imidazo[4,5-c]pyridine 99
[00465] Light brown solid (18.2 mg, 14.2% yield). 111 NMR (DMSO-d6, 500
MHz) 3 ppm 2.39 (s, 3H), 7.36 (t, J=8.5Hz, 2H), 7.50 (d, J=5Hz, 1H), 7.62 (dd,
J=8.5Hz,
J=1.5Hz, 1H), 7.85 (d, J=8.5Hz, 111), 8.28 (brs, 2H), 8.54 (d, J=3.5Hz, 2H),
8.58 (s, 1H),
8.71 (s, 1H), 9.06 (brs, 1H), 14.21 (s, 111); ESIMS found C251117FN6 intz
421.0 (M-41).
F
0,,J-NH
N\ NH
N
\N
102
1004661 N-(5-(3-(7-(4-Fluoropheny1)-3H-imidazo[4,5-c]pyridin-2-y1)-111-
indazol-5-yl)pyridin-3-yl)pivalamide 102
[00467] Tan solid (66.3 mg). 111 NMR (DMSO-d6, 500 MHz) 6 ppm 1.30 (s,
9H), 7.38 (t, J=8.5Hz, 2H), 7.85 (s, 211), 8.48 (brs, 211), 8.62 (brs, 1H),
8.67 (s, 2H), 8.83
(s, 111), 8.85 (brs, 111), 8.90 (s, 1H), 9.62 (s, 1H), 13.76 (brs, 111), 14.03
(s, 1H); ESIMS
found C29H24FN70 fritz 506.1 (M+H).
/ N
0 NH
N\ NH
N
\N
104
118

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1004681 N-(5-(3-(7-(4-Fluoropheny1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3 -yl)benzamide 104
1004691 Light brown solid (1.1 mg, 0.002 minol, 2.4% yield). 111 NMR
(DMSO-d6, 500 MHz) 8 ppm 7.39 (t, J=9Hz, 211), 7.59 (t, J=7.5Hz, 2H), 7.65 (d,
J=7Hz,
1H), 7.89 (s, 2H), 8.06 (dd, J=1Hz, J=8.5Hz, 211), 8.47 (brs, 214), 8.70 (brs,
1H), 8.75 (s,
111), 8.88 (s, 111), 8.91 (brs, 1H), 8.99 (s, 111), 10.69 (s, 111), 14.12 (s,
1H); ESIMS found
C311120FN70 m/z 526.3 (M+H).
N
N\ NH
I
N*
N
107
[00470] 7-(4-Fluoropheny1)-2-(5 -(5 -(pyrro1idin-1 -ylmethyppyri din-3-y1)-1H-
indazol-3 -y1)-3 H-imidazo [4,5-c] pyridine 107
[00471] Brown solid (12.7 mg, 57% yield). IF1 NMR (DMSO-d6, 500 MHz) 6
ppm 1.71 (brs, 4H), 2.47-2.56 (m, 411), 3.76 (s, 211), 7.41 (t, J=9Hz, 2H),
7.83 (d,
J=8.5Hz, 1H), 7.93 (d, J=9Hz. 111), 8.07 (s, 1II), 8.45 (t, J=6Hz, 2H), 8.56
(s, 1H), 8.66
(s, 111). 8.84 (s, 1H), 8.90 (s, 111), 8.92 (s, 111), 13.72 (brs, 1H), 14.00
(brs, 111); ESIMS
found C29H24FN7 miz 490.2 (M+II).
I F
/ N
0 NH
N\ NH
N
\N
111
[00472] N-(5-(3 -(744 -Fluoropheny1)-3H-imidazo [4,5 -c]pyridin -2 -y1)-1H-
indazol-5-yl)pyridin-3 -yl)cyclobutanecarboxamide 111
[00473] Brown solid (4.1 mg, 0.008 mmol, 22.0% yield). 11-1NMR (DMSO-d6,
500 MHz) 6 ppm 1.25-1.36 (m, 111), 1.43-1.53 (m, 111), 1.77-1.88 (m, 1H), 1.93-
2.02 (m,
1H), 2.13-2.22 (m, 111), 2.25-2.34 (m, 1H), 2.84-2.95 (m, 111), 7.35 (brs,
211), 7.40 (t,
1 1 9

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J=9Hz, 2H), 7.84 (s, 2H), 8.19 (brs, 1H), 8.47 (brs, 1H), 8.63 (brs, 1H), 8.66
(dõf=1.5Hz,
1H), 8.73 (brs, 1H), 8.84 (brs, 1H), 10.17 (s, 1H), 13.74 (brs, 1H); ESIMS
found
C29H22FN70 m/z 504.1 (M+H).
/ N
NH
\ NH
N
\N
N
124
[00474] 543- (7-(2-Fluoropheny1)-3H-imidazo [4,5-c] pyridin-2-y1)-1H-indazol-
5-y1)-N-isopropylpyridin-3 -amine 124
[00475] Tan solid (11.1 mg, 0.024 mmol). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.14-1.26 (m, 6H), 3.59-3.77 (m, 111), 5.80-5.90 (m, 1H), 7.10, 7.20 (2
rotamers,
1H), 7.32-7.43 (m, 2H), 7.48-7.59 (m, 1H), 7.77 (s, 2H), 8.03-8.13 (m, 1H),
8.30, 8.49 (2
rotamers, 1H), 8.68, 8.69 (2 rotamers, 1H), 8.88, 9.10 (2 rotamers, 1H),
13.66, 13.68 (2
rotamers, 1H), 13.87, 13.94 (2 rotamers, 1H); ESIMS found C271122FN7 m/z 463.9
(M+H).
/ N
N\ NH
N
/111
127
[00476] 7-(2-
Fluoropheny1)-2-(5-(5-(piperi din-1 -ylmethyl)pyridin-3-y1)-111-
indazol-3 -y1)-311-imidazo [4,5-c]pyri dine 127
[00477] Brown solid (53.7 mg, 39% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.36-1.57 (m, 6H), 2.42 (in, 4H), 3.61 (s, 2H), 7.35-7.46 (m, 2H), 7.50-
7.58 (m, 1H),
7.82 (d, J=9Hz, 1H), 7.88 (d, J=7.5Hz, 1H), 7.97 (s, 1H), 8.16 (t, J=8Hz, 1H),
8.52 (d,
J=7.5Hz, 2H), 8.79 (s, 1H), 8.86 (s, 1H), 13.71 (s, 1H), 13.99 (s, 1H); ESIMS
found
C30H26FN7 m/z 504.3 (M+H).
120

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/N
\ NH
N
I N\)4
H
136
[00478] 7-(Pyridin-3 -y1)-2- (5 -(pyridin-3-y1)-1H-indazol-3-y1)-3H-
imidazo [4,5-
c]pyridine 136
[00479] Light brown solid (35.1 mg, 51.5% yield). 111 NMR (DMSO-d6, 500
MHz) 6 ppm 7.56-7.64 (m, 211), 7.85 (d, J-8.5Hz, 111), 7.90 (d, J=10Hz, 111),
8.19 (td,
J=1.5Hz, J=8Hz, 1H), 8.64 (dd, J=4.5Hz, J-1.5Hz, 1H), 8.69 (ddõI=5Hz, J.---
1.5Hz, 1H),
8.77 (brs, 211), 8.86 (s, 1H), 8.95 (brs, 1H), 9.01 (d, J=1.5Hz, 111), 9.52
(brs, 1H), 14.06
(s, 1H); ESIMS found C23H15N7 m/z 389.8 (M+H).
z N
\ NH
I
N
zN
154
[00480] 2-(5-(4-Methylpyridin-3-y1)-111-indazol-3-y1)-7-(pyridin-4-y1)-
3H-
imidazo[4,5-c]pyridine 154
[00481] Light yellow solid (2.7 mg, 3.0% yield). 11-1 NMR (DMSO-d6, 500
MHz) 6 ppm 2.42 (s, 3H), 7.45 (d, J=5Hz, 111), 7.61 (d, J-9Hz, 1H), 7.83 (d,
J=8.5Hz,
111), 8.36 (d, J-5.5Hz, 2H), 8.50 (d, J=5.511z, 1H), 8.56 (s, 111), 8.61 (s,
1H), 8.65 (d,
J-5Hz, 111), 8.81 (s, 111), 8.92 (s, 111), 13.85 (s, 1H), 14.05 (s, 1H); ESIMS
found
C24E-117N7 in/z 404.1 (M+H).
ON N/
/ N
N \ NH
N
163
121

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[00482] 7-(Pyridin-4-y1)-2-(5 -(5 -(pyrrolidin-1-ylmethyl)pyridin-3-y1)-
1H-
indazol-3 -y1)-3 H-imidazo [4,5-c] pyridine 163
[00483] Brown solid (9.7 mg, 70% yield). 11-1 NMR (DMSO-d6, 500 MHz) 8
ppm 1.73 (brs, 4H), 2.51-2.62 (m, 4H), 3.76 (s, 2H), 7.85 (d, J=8.5Hz, 1H),
7.94 (d,
J=9Hz, 1H), 8.11 (s, 11-1), 8.47 (d, J=4Hz, 2H), 8.56 (s, 1H), 8.77 (d, J=4Hz,
2H), 8.85 (s,
114), 8.93 (brs, 3H), 13.85 (brs, 1H), 14.04 (brs, 1H); ES1MS found C28H24N8
nalz 473.3
(M+14).
ThN/
N\ NH
\
NiN
164
[00484] 2-(5 -(5 -(Piperidin-1-ylmethyl)pyridin-3 -y1)-1H-indazol-3-y1)-7-
(pyridin-4-y1)-3H-imidazo [4,5-c]pyridine 164
[00485] Brown solid (70 mg, 73% yield). 11-1 NMR (DMSO-d6, 500 MHz) 8
ppm 1.40 (brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.63 (brs, 211), 7.85 (d,
J=8.5Hz, 1H),
7.92 (d, J=8.5Hz, HI), 8.08 (s, 1H), 8.46 (d, J=5.5Hz, 2H), 8.54 (s, 1H), 8.76
(d,
J=5.51-1z, 2H), 8.84 (s, 1H), 8.90-8.97 (m, 3H), 13.85 (brs, 1H), 14.04 (brs.
1H); ESIMS
found C29H26N8 M/Z 487.1 (M+H).
N
0 NH
N\ NH
I
N
170
[00486] N-(5-(3 -(7-(Pyridin-4-y1)-3H-imidazo [4,5-c] pyridin-2 -y1)-1H-
indazol-
5-yl)pyridin-3-yeeyelopentaneearboxamide 170
[00487] Tan solid (30.2 mg, 0.06 mrnol). 1H NMR (DMSO-d6, 500 MHz) 8
ppm 1.54-1.65 (m, 2H), 1.65-1.76 (m, 211), 1.76-1.87 (m, 211), 1.88-1.98 (m,
21-1), 2.88
(quin, J=8Hz, 1H), 7.86 (s, 2H), 8.46 (d, J=4.5Hz, 2H), 8.66 (s, 1H), 8.68 (s,
111), 8.70-
122

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8.77 (m, 3H), 8.86 (s, 1H), 8.88 (s, 1H), 8.93 (s, 1H), 10.30 (s, 1H), 13.86
(brs, 1H),
14.06 (s, 1H); ESIMS found C29H241\180 inlz 501.2 (M+H).
N/ N
HN
N\ NH
\N
Ni
173
[00488] 1-Cyclopenty1-N-((5-(3 -(7-(pyridin-4-y1)-3 H-imidazo [4,5-c]
pyridin-2-
y1)-1H-indazol-5-y1)pyridin-3-y1)methyl)methanamine 173
[00489] Brown solid (1.7 mg, 0.003 mmol, 2.5% yield). 1H NMR (DMSO-d6,
500 MHz) 8 ppm 1.41-1.63 (m, 8H), 1.79 (brs, 1H), 3.01 (brs, 2H), 4.34 (brs,
2H), 7.84-
7.89 (m, 1H), 7.92 (d. J=5.5Hz, 1H), 8.41 (s, 1H), 8.47 (d, J=611z, 2H), 8.75
(s, 1H), 8.76
(d, J=6Hz, 2H), 8.86 (s, 1H), 8.94 (s, 1H), 8.98 (s, 1H), 9.11 (s, 111), 13.81
(brs, 1H),
14.11 (s, 111); ESIMS found C301128N8 m/z 501.3 (M+1-1).
N
CNH
N\ NH
\ N
174
[00490] N-(5-(3 -(7-(Pyridin-2-y1)-3H-imidazo [4,5 -c]pyridin-2-y1)-1H-indazol-
5-yl)pyridin-3-yl)propionamide 174
[00491] Tan solid (40.1 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.15 (t,
J=7.5Hz, 3H), 2.44 (q, J=71-1z, 2H), 7.47 (brs, 1H), 7.89 (s, 2H), 8.03 (t,
J=7.5Hz, 1H),
8.59 (brs, 1H), 8.69 (s, 1H), 8.75(brs, 1H), 8.83 (brs, 1H), 9.03 (brs, 1H),
9.21 (brs, 2H),
10.30 (s, 1H), 14.10 (s, 1H); ESIMS found C26H201\180 miz 461.1 (M+H).
II
/ N
N\ NH
N
123

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177
[00492] 7-(Pyridin-2-y1)-2-(5-(pyridin-3-y1)-1H-indazol-3-y1)-3H-
imiciazo [4,5-
c]pyridine 177
[00493] White solid (32.4 mg, 41.6% yield). 1H NMR (DMSO-d6, 500 MHz) 8
ppm 7.51 (dd, J=7Hz, J=5Hz, 1H), 7.61 (dd, J=7.5Hz, J=5Hz, 111), 7.87 (d,
J=8.5Hz,
1H), 7.92 (d. J=9Hz, 1H), 8.02 (t, J=7.5Hz, 1H), 8.23 (d, J=8Hz, 1H), 8.65 (d,
J=4I1z,
111), 8.84 (brs, 111), 8.90 (brs, 1H), 9.05 (brs, 2H), 9.20 (brs, 211), 14.09
(s, 111); ESIMS
found C231115N7 nilz 390.2 (M+H).
N
/ N
N\ NH
\ N
186
[00494] N,N-Dimethy1-1-(5-(3-(7-(pyridin-2-y1)-311-imidazo [4,5-c]pyridin-2-
y1)-1H-indazol-5-yl)pyridin-3-yl)methanamine 186
[00495] Light brown solid (18.4 mg, 25.8% yield). 1H NMR (DMSO-d6, 500
MHz) 3 ppm 2.84 (s, 611), 4.47 (s, 211), 7.52 (dd, J=6.5Hz, J=4.5Hz, 1H), 7.92
(s, 2H),
8.02 (t, J=7Hz, 1H), 8.38 (s, 111), 8.73 (s. 1H), 8.80-9.26 (m, 6H), 14.17
(brs, 111);
ESIMS found C26H22Ng 171/Z 447.0 (M+H).
N
0NH
N\ NH
N \N
199
[00496] 3-Methyl-N-(5-(3-(7-(piperidin-1-y1)-3H-imidazo [4,5-c]pyridin-
2-y0-
1H-indazol-5-y1)pyridin-3-y1)butanamide 199
[00497] Brown solid (22.7 mg, 22.2% yield). 111 NMR (DMSO-d6, SOO MHz)
6 ppm 0.98 (d, J=6.5Hz, 611), 1.52-1.64 (m, 611), 2.13 (sep, J=7Hz, 111), 2.28
(d,
J=7.5Hz, 2H), 3.38-3.52 (m, 4H), 6.67 (s, 1H), 7.79 (s, 211), 8.36 (d,
J=2.511z, 1H), 8.63
124

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(dd, j=5Hz, J=2Hz, 214), 8.66 (s, 114), 8.85 (d, J=2Hz, 111), 10.26 (s, 114),
12.88 (s, 1H),
13.80 (s, 111); ESIMS found C28H30N80 mtz 495.4 (M+H).
N \ NH
N
\N
202
[00498] 2-(5-(4-Methylpyridin-3-y1)-1H-indazol-3-y1)-7-(piperidin-l-y1)-3H-
imidazo[4,5-c]pyridine 202
[00499] White solid (1.5 mg, 1.1% yield). 114 NMR (DMSO-d6, 500 MHz) 8
ppm 1.65 (brs, 614), 2.38 (s, 3H), 3.51 (brs, 4H), 7.02 (brs, 1H), 7.59 (dd,
J=9Hz,
J=1.514z, 114), 7.65 (d, 1H), 7.85 (d, J=8.511z, IH), 8.43 (s, 111), 8.64
(brs, 211),
8.71 (brs, 111), 13.76 (brs, 111), 14.21 (s, IH); ESIMS found C24H23N7 inlz
410.1 (M+H).
N
0NH
N\ NH
N
\ N
N/
205
[00500] N-(5-(3-(7-(Piperidin-l-y1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-
indazol-5-yppyridin-3-yDpivalamide 205
[00501] Tan solid (66.5 mg). 114 NMR (DMSO-d6, 500 MHz) 6 ppm 1.29 (s,
9H), 1.60 (brs, 6H), 3.48 (brs, 4I1), 6.67 (s, 114), 7.80 (s, 214), 8.41 (t,
J=2Hz, 111), 8.63
(d, J=1.5Hz, 1H), 8.64 (s, 11-1), 8.67 (s, 1H), 8.97 (d, J=2Hz, 114), 9.59 (s,
1H), 12.89 (s,
1II), 13.81 (s, 1H); ESIMS found C28H3 ON8 0 M/Z 495.5 (M+H).
ay N\
)NH
N
\ N
211
125

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[00502] 7-(Piperidin-
l-y1)-2-(5-(5-(pyrrolidin-l-ylmethyl)pyridin-3-y1)-1H-
indazol-3-y1)-3H-imidazo[4,5-c]pyridine 211
[00503] Brown solid (17.1 mg, 53% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.61 (brs, 6H), 1.74 (brs, 4H), 2.48-2.56 (m, 4H), 3.48 (brs, 4H), 3.75
(s, 211), 6.67
(s, 1H), 7.81 (q. J=9.5Hz, 2H), 8.04 (s, 1H), 8.53 (s, 111), 8.63 (s, 111),
8.68 (s, 1H), 8.84
(s, 1H), 12.88 (brs, 1H), 13.79 (brs, 1H); ESIMS found C281130N8 inlz 479.3
(M+H).
o NH
ON z N
N\ NH
N
\ N
NI
214
[00504] N-(5-(3-(7-(Piperidin-1-y1)-3H-imidazo [4,5-c] pyridin-2-y1)-1H-
indazol-5 -yl)pyri din-3 -y1)butyrami de 214
[00505] Brown solid (33.2 mg, 0.069 mmol). 1H NMR (DMSO-d6, 500 MHz)
6 ppm 0.96 (t, J=7.5Hz, 3H), 1.61 (brs, 611), 1.66 (sex, J=7.5Hz, 2H), 2.38
(t, J-7.5Hz,
2H), 3.48 (brs, 4H), 6.67 (s, 1H), 7.79 (s, 211), 8.36 (s, 1H), 8.62 (s, 1H),
8.63 (s, 1H),
8.66 (s, 1H), 8.85 (d, J=1.5Hz, 111), 10.27 (s, 1H), 12.88 (s, 1H), 13.80 (s,
1H); ESIMS
found C27H281\180 m/z 481.0 (M+H).
0NH
N\ NH
NI
217
[00506] N-(5-(3-(7-(Piperidin-1-y1)-311-imidazo [4,5-c] pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3 -ypeyclobutanecarboxamide 217
[00507] Beige solid (12 mg, 0.024 mmol, 46.9% yield). 1H NMR (DMSO-d6,
500 MHz) 6 ppm 1.61 (brs, 611), 1.80-1.88 (m, 111), 1.93-2.04 (m, 1H), 2.11-
2.21 (m,
2H), 2.22-2.33 (m, 211), 3.26-3.32 (m, 1H), 3.48 (brs, 4H), 6.67 (s, 111),
7.79 (s, 2H), 8.37
126

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(d, J=2Hz, 1H), 8.62 (d, J=2Hz, 1H), 8.64 (s, 1H), 8.66 (s, 114), 8.87 (d,
J=2Hz, 1H),
10.12 (s, 1H), 12.88 (s, 1H), 13.80 (s, 1H); ESIMS found C28H28N80 m/z 493.2
(M+H).
/
NH2
\ NH
NI
N
247
[00508] 5 -(3-(7-(4-Methylpiperazin-l-y1)-314-imid azo [4,5-c]pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3 -amine 247
[00509] Tan solid (9.6 mg). 114 NMR (DMSO-d6, 500 MHz) 6 ppm 2.36 (s,
3H), 2.44-2.56 (m, 4H), 3.46 (brs, 4H), 5.50 (s, 2H), 6.70 (s, 114), 7.26 (t,
J=2Hz, 114),
7.65-7.76 (m, 2H), 7.96 (d, J=2Hz, 1H), 8.09 (d, J=1.5Hz, 1H), 8.62 (s, 1H),
8.65 (s, 114),
12.95 (s, 1H), 13.76 (s, 114): ESIMS found C23H23N9 m/z 426.4 (M+H).
=
/
0 NH
N\ NH
\ N
252
[00510] N-(5-(3 -(7-(4 -Methylpiperazin-1 -y1)-3 H-imidazo [4,5 -c] pyridin-2-
y1)-
IH-indazol-5 -yl)pyridin-3 -y1)-2-phenyl acetamide 252
[00511] Beige solid (7.0 mg, 4.5% yield). 11-1 NMR (DMSO-d6, 500 MHz) 6
ppm 2.24 (s, 3H), 2.46 (brs, 5H), 3.45 (brs, 314), 3.74 (s, 2H), 6.69 (s, 1H),
7.27 (t,
J=5.5Hz, 1H), 7.32-7.41 (m, 4H), 7.79 (s, 2H), 8.36 (s, 1H), 8.64 (s, 2H),
8.66 (s, 1H),
8.86 (d, J=2.5Hz, 1H), 10.58 (s, 1H), 12.96 (s, 1H), 13.82 (s, 1H); ESIMS
found
C311429N90 m/z 544.2 (M+H).
127

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>) 'NON
C:eNH
N
\ NH
NI
\ N
257
[00512] 3,3 -Dimethyl-N-(5 -(3 -(7-(4-methylpiperazin-l-y1)-3H-imidazo [4,5-
c]pyridin-2-y1)-1H-indazol-5 -yl)pyridin-3 -yl)butanamide 257
[00513] White solid (65.7 mg, 23.0% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.06 (s, 9H), 2.24 (s, 4H), 2.28 (s, 2H), 2.46 (brs, 4H), 3.45 (brs, 3H),
6.69 (s, 1H),
7.79 (ABq, J=10.5Hz, 2H), 8.37 (t, J=2Hz, 1H), 8.65 (dt, J=9.5Hz, J=2Hz, 3H),
8.85 (d,
J=2Hz, 1H), 10.2 (s, 1H), 12.97 (s, 1H), 13.82 (s, 1H); ESIMS found C29H33N90
liz/z
524.3 (M+H).
IYON
rs\1
N\ NH
N
\ N
260
[00514] N-(5-(3 -(7-(4-Methylpiperazin-1 -y1)-3 H-imidazo [4,5-clpyridin-2-y1)-
1H-indazol-5 -yl)pyridin-3 -yl)cyclopropanecarboxamid e 260
[00515] Brown solid (30.0 mg, 15.1% yield). 1H NMR (DMSO-d6, 500 MHz)
6 ppm 0.83-0.91 (m, 4H), 1.80-1.87 (m, 1H), 2.24 (s, 3H), 2.47 (brs, 5H), 3.45
(brs, 3H),
6.69 (s, 1H), 7.78 (ABq, J=9Hz, 2H), 8.36 (d, J-2Hz, 1H), 8.62 (d, J=2Hz, 1H),
8.66 (d,
J--2Hz, 2H), 8.84 (d, J=2Hz, 1H), 10.60 (s, 1H), 12.96 (s, 1H), 13.82 (s, 1H);
ESIMS
found C27H27N90 m/z 494.4 (M+H).
----NoN N
1
2H
N\ NH
N
\N
128

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263
1005161 N-(5-(3 -(7-(4-Methylpiperazin-1 -y1)-3H-imidazo [4,5 -c]pyri din-2-
y1)-
1H-indazol-5-yppyridin-3 -yl)cyclohexaneearboxamide 263
[00517] Brown solid (L7 mg, 2.2% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 1.16-1.26 (m, 511), 1.31 (q, 1=12.511z, 211), 1.45 (q, J=9.5Hz, 311), 1.67
(d, J=12Hz,
1H), 1.78 (d, J=18Hz, 211), 1.87 (d, J=12Hz, 2H), 2.23-2.51 (m, 6H), 3.44
(brs, 3H), 6.70
(1H), 7.79 (ABq, J=13.5Hz, 211), 8.38 (s, 111), 8.60 (d, J=2Hz, 111), 8.64 (d,
J=4Hz, 211),
8.84 (d, J=2Hz, 1H), 10.20 (s, 1H), 12.99 (brs, 1H), 13.82 (s, 111); ESIMS
found
C301433N90 M/Z 536.3 (M+H).
1
NH2
N\ NH
NI
\N
268
[00518] 5-(3 -(3H-Imidazo [4,5 -c]pyridin-2-y1)-1H-indazol -5-
yl)pyridin-3 -
amine 268
[00519] Tan solid (81.6 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 7.54 (brs,
1H), 7.81 (dd, J=8.5Hz, J=1.5Hz, 1H), 7.89 (d, J=9Hz, 111), 8.02 (d, J=2.5Hz,
2H), 8.24
(s, 1H), 8.56 (dõ,T=6Hz, 11-I), 8.68 (s, 1H), 14.31 (s, 111); ESIMS found
Ci8Hi3N7 m/z
328.1 (M41).
a
o75N\ NH
274
[005201 N-(5 -(3 -(3H-Imidazo [4,5-c]pyridin-2-y1)-1H-indazol-5-yl)pyridin-3 -
y1)-2-phenylacetamide 274
[00521] Beige solid (19.0 mg, 10.3% yield). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 3.74 (s, 211), 7.27 (t, J=7Hz, 1H), 7.32-7.40 (m, 41-1), 7.52 (d, J=5.5Hz,
1H). 7.81
(ABq, J=11.5Hz, 2H), 8.34 (d, J=5.5Hz, 1H), 8.38 (t, J=2Hz, 1H), 8.65 (d,
J=2Hz, 1H),
129

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8.86 (dõ./=1.5Hz, 1H), 9.05 (s, 1H), 10.58 (s, 1H), 13.48 (brs, 1H), 13.95
(brs, 1H);
ESIMS found C26H19N70 m/z 446.3 (M+H).
0 NH
N\ NH
N
\N
275
[00522] N-(5-(3 -(3H-Imidazo [4,5 -c] pyridin-2-y1)-1H-indazol-5 -yl)pyridin-3
-
yObenzami d e 275
[00523] Light brown solid (2.1 mg, 0.005 mmol, 3.1% yield). 1H NMR
(DMSO-d6, 500 MHz) 6 ppm 7.57 (dt, J=2Hz, J=7.5Hz, 211), 7.64 (dd, .1=2.5Hz,
J-7.5Hz, 2H), 7.86 (s, 2H), 8.05 (dd, J=1.5Hz, J=8.51-1z, 2H), 8.35 (d, J-
5.5Hz, 1H),
8.57 (dt, J=2Hz, J=4Hz, 1H), 8.72 (d, J=2Hz, 1H), 8.76 (s, 1H), 9.04 (d,
J=2Hz, 1H),
9.09 (d, J=2Hz, 11-1), 10.64 (s, 1H), 14.02 (s, 1H); ESIMS found C25H17N70 m/z
432.3
(M+H).
0 NH
N\ NH
N
\N
N/
280
[00524] N-(5-(3-(3H-Imidazo[4,5-c]pyridin-2-y1)-1H-indazol-5-yl)pyridin-3-
y1)-3,3-dimethylbutanamide 280
[00525] Light brown solid (12.2 mg, 10.9% yield). 1H NMR (DMSO-d6, 500
MHz) 6 ppm 1.07 (s, 911), 2.29 (s, 2H), 7.85 (dd, J=9Hz, J=1.5Hz, 1H), 7.92
(d, J=8.5Hz,
III), 8.06 (brs, 1H), 8.49 (s, 1H), 8.62 (d, J=6.5Hz, 1H), 8.67 (dd, J=7Hz,
J=1.5Hz, 2H),
8.82 (d, 1=1.5Hz, 1H), 9.58 (brs, 1H), 10.28 (s, 1H), 14.35 (s, 1H), 14.78
(brs, 1I1);
ESIMS found C24H23N70 m/z 426.1 (M+H).
130

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0YNH / N
\ NH
\N
283
[00526] N-(5-(3-(3H-Imidazo[4,5-c}pyridin-2-y1)-1H-indazol-5-yppyridin-3-
y1)eyelopropanecarboxamide 283
[00527] Yellow white solid (5.7 mg, 2.3% yield). 1H NMR (CD30D, 500
MHz) 8 ppm 0.91-0.96 (m, 2H), 1.02-1.07 (m, 2H), 1.86 (quin, J=3.5Hz, 1H),
7.21 (sd,
J=1.5Hz, 1H), 7.69 (t, J=1.5Hz, 1H), 7.73 (d, J=8.5Hz, 1H), 7.78 (dd, J=7.5Hz,
J-1.5Hz,
1H), 8.50 (s, 1H), 8.59 (t, J=2Hz, 1H), 8.65 (d, J=2Hz, 2H), 8.71 (d, J=2Hz,
2H), 8.84 (s,
111); ESIMS found C22H17N70 !viz 396.3 (M+11).
N
0 NH
N\ NH
NI
\N
N/
286
[00528] N-(5-(3 -(3H-Imid azo [4,5-c] pyridin-2-y1)-1H-indazol-5-yl)pyridin-3 -

ypeyclohexaneearboxamide 286
[00529] Light brown solid (31.2 mg, 13.3% yield). 1H NMR (DMSO-d6, 500
MHz) 8 ppm 1.16-1.34 (m, 3H), 1.45 (dq, J=12.5Hz, J=3Hz, 21I), 1.67 (d, 1-
17Hz, 1H),
1.79 (d, J=13Hz, 2H), 1.87 (d, J=12.5Hz, 2H), 2.41 (t of quin, J=11.5Hz,
J=3.5Hz, 111),
7.53 (brs, 1H), 7.82 (dq, J=9Hz, 1=1.5Hz, 2H), 8.34 (d, 5Hz, 1H), 8.40 (t,
J=2Hz, 1H),
8.62 (d, J=2Hz, 1H), 8.70 (s, 111), 8.85 (d, J=2Hz, 1H), 9.07 (brs, 1H), 10.21
(s, 1H),
13.51 (brs, 1H), 13.99 (s, 1H); ESIMS found C25H23N70 m/z 438.0 (M H).
131

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s / N
0NH
N\ NH
N
\N
289
[00530] N-(5-(3-(7-(Thiophen-3-y1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-
indazol-5-yl)pyridin-3-y1)propionamide 289
[00531] Tan solid (24.9 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 1.16 (t,
J=7.5Hz, 3H), 2.46 (qõI=7.5Hz, 2H), 7.76 (dd, J=4.5Hz, J=3Hz, 1H), 7.88 (s,
2H), 8.15
(brs, 1H), 8.65 (brs, 1H), 8.69 (s, 1H), 8.71 (s, 1H), 8.78 (brs, 1H), 8.82-
8.93 (m, 3H),
10.30 (s, 11-1), 14.13 (s, 1H); ESIMS found C25Hi9N70S m/z 466.2 (M+H).
s
NH2
N\ NH
N
\ N
291
[00532] 5-(3-(7-(Thiophen-3-y1)-31-1-imidazo[4,5-clpyridin-2-y1)-1H-
indazol-
5-yl)pyridin-3-amine 291
[00533] Tan (11.9 mg). 1H NMR (DMSO-d6, 500 MHz) 6 ppm 5.49 (s, 2H),
7.31 (s, 1H), 7.70-7.83 (m, 3H), 7.99 (s, 1H), 8.17 (s, 1H), 8.22 (d, J=4.5Hz,
1H), 8.74 (s,
1H), 8.78 (s, 1H), 8.82 (s, 1H), 8.83 (s, 1H), 13.67 (s, 1H), 13.97 (s, 1H);
ESIMS found
C22HL5N7S m/z 410.1 (M+H).
/¨
s z N
\ NH
N
I /N
N
293
[00534] 2-(5-(4-Methylpyridin-3-y1)-1H-indazol-3-y1)-7-(thiophen-3-y1)-311-
imidazo[4,5-c]pyridine 293
132

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[00535] Light brown solid (36.0 mg, 35.0% yield). 111 NMR (DMSO-d6, 500
MHz) 6 ppm 2.47 (s, 3H), 7.66 (dd, J=9.5Hz, J=5 .5Hz, 111), 7.68 (d, J-1.5Hz,
1H), 7.80
(q, J-3Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 8.16 (brs, 1H), 8.56-8.64 (m, 2H), 8.70
(s, 1H),
8.82 (brs, 1H), 8.96 (s, 1H), 9.10 (s, 1H), 14.41 (s, 1H); ESIMS found
C23Hi6N6S m/z
409.4 (M+H).
s /
N\ NH
NI
NN
N/
295
[00536] N,N-Dimethy1-5-(3-(7-(thiophen-3-y1)-3H-imidazo[4,5-c]pyridin-2-
y1)-1H-indazol-5-y1)pyridin-3-amine 295
[00537] Tan solid (28.8 mg, 0.066 mmol). 1H NMR (DMSO-d6, 500 MHz) 6
ppm 3.09 (s, 6H), 7.43 (s, 1H), 7.73 (dd, J=4.5Hz, J=7.5Hz, 2H), 7.83 (d,
J=8.5Hz,111),
7.90 (dd, 1=1.5Hz. J=9Hz, 1H), 8.17 (brs, 1H), 8.19 (d, J=3Hz, 1H), 8.32 (s,
111), 8.80
(brs, 1H), 8.82 (s, 1H), 8.87 (s, 1H), 13.81 (brs, 1H), 14.02 (s, 1H); ESIMS
found
C24Hi9N7S m/z 438.1 (M+H).
s 7 N
N\ NH
N
l\/N
301
[00538] N,N-Dimethy1-1-(5-(3-(7-(thiophen-3-y1)-3H-imidazo[4,5-dpyridin-2-
34)-1H-indazol-5-yppyridin-3-y1)methanamine 301
[00539] Brown solid (45 mg, 43.3% yield). 11-1 NMR (DMSO-d6, 500 MHz) 6
ppm 2.24 (s, 6H), 3.59 (d, 1=31-1z, 2H), 7.75 (dd, 1=3Hz, 1H),
7.85 (d, J=8.5Hz,
1H), 7.93 (d, J=10.5Hz, 1H), 8.09 (s, 1H), 8.20 (d, J=5Hz, 1H), 8.54 (ABq,
J=10.5Hz,
1H), 8.78 (s, 1H), 8.79 (s, 1H), 8.82 (s, 1H), 8.91 (s, 1H), 8.94 (d, J=2Hz,
1H), 13.69 (s,
1H), 14.01 (s, 1H); ESIMS found C25H2IN7S m/z 452.0 (M+H).
133

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N\ NH
N
\N
Ni
303
[00540] 2-(5-(5-(Piperidin-1-ylmethyl)pyridin-3-y1)-1H-indazol-3-y1)-7-
(thiophen-3-y1)-3H-imidazo[4,5-c]pyridine 303
[00541] Brown solid (92.8 mg, 52% yield). 1H NMR (DMSO-d6, 500 MHz) 8
ppm 1.39 (brs, 2H), 1.51 (brs, 4H), 2.43 (brs, 4H), 3.64 (s, 2H), 7.75 (t, J---
-4.5Hz, 1H),
7.85 (d, J=8Hz, 111), 7.92 (d, J=9Hz, 1H), 8.08 (s, 1H), 8.19 (d, J=5IIz, 1H),
8.54 (s, 1H),
8.79 (s, 2H), 8.81 (s, 1H), 8.92 (s, 211), 13.69 (brs, 1H), 14.01 (brs, 111);
ESIMS found
C28H25N7S m/z 492.3 (M+H).
r¨
s N
OH
N
\ NH
Ncj
304
[00542] 3,3-Dimethyl-N-(5-(3-(7-(thiophen-3-y1)-3H-imidazo[4,5-
c]pyridin-2-
y1)-1H-indazol-5-yl)pyridin-3-yl)butanamide 304
[00543] Brown solid (15 mg, 26.2% yield). ]1-1NMR (DMSO-d6, 500 MHz) 8
ppm 1.07 (s, 911), 2.32 (s, 2H), 7.84 (dt, J=3Hz, J=5Hz, 1H), 7.90 (d, J=911z,
111), 7.94
(d, J=8.5Hz, 1H), 8.23 (brs, 1H), 8.66 (brs, 1H), 8.73 (s, 1 H) , 8.76 (s,
111), 8.84 (s, 111),
8.94 (brs, 1H), 9.00 (brs, 1H), 9.11 (brs, 11-1), 10.30 (s, 1H), 14.42 (s,
1H), 14.93 (brs,
1H); ESIMS found C281-125N70S m/z 508.2 (M+H).
C1) si / N
HN
N\ NH
N
\ N
Ni
134

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311
[00544] 1-Cyclopentyl-N4(5-(3-(7-(thiophen-3-y1)-3H-imidazo[4,5-
c]pyridin-
2-y1)-1H-indazol-5-yl)pyridin-3-y1)methyl)methanamine 311
[00545] Light brown solid (4.9 mg, 0.01 mmol, 5.4% yield). IHNMR (DMSO-
d6, 500 MHz) 6 ppm 1.13-1.26 (m, 2H), 1.39-1.56 (m, 4H), 1.70 (brs, 2H), 2.01
(t,
J=7.5Hz, 1H), 3.92 (s, 2H), 7.76 (dd, J=3Hz, 1H),
7.85 (d, J=8.5Hz, 1H), 7.92 (d,
J=8.5Hz, 1H), 8.19 (brs, 1H), 8.22 (d, J=4.511z, 1H), 8.59 (s, 1H), 8.79 (s,
2H), 8.82 (s,
1H), 8.92 (s, 1H), 8.95 (s, 1H), 14.01 (brs, 1H); ESIMS found C29H27N7S m/z
506.0
(M+H).
N
N\ NH
N
315
[00546] 7-(Furan-3 -y1)-2-(5 -(pyridin-3-y1)-1H-indazol-3-y1)-311-
imidazo [4,5-
c]pyridine 315
[00547] Brown solid (68 mg, 77.5% yield). 11-1NMR (DMSO-d6, 500 MHz) 6
ppm 7.44 (d, J=1.5Hz, 1H), 7.59 (dd, J=8Hz, J=5Hz, 1H), 7.87 (q, J----9Hz,
2H), 7.89 (s,
1H), 8,21 (dd, J=11Hz, J=2Hz, 1H), 8.63 (dd, J=9.5Hz, J=1.5Hz, 1H), 8.71 (s,
1H), 8.76
(s, 1H), 8.86 (d, J=10Hz, 21-1), 9.03 (d, J-2.5Hz, 1H), 13.65 (s, 1H), 14.01
(s, 1H);
ESIMS found C22Hi4N60 mlz 379.1 (M+H).
o N
N\ NH
N
I N
319
[00548] N-(5-(3-(7-(Furan-3-y1)-3H-imidazo[4,5-c]pytidin-2-y1)-1H-indazol-5-
yl)pyridin-3-yl)pivalamide 319
135

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[00549] Tan solid (42.2 mg). 11-I NMR (DMSO-d6, 500 MHz) 6 ppm 1.30 (s,
9H), 7.83 (s, 1H), 7.86 (s, 2H), 8.59 (s, 1H), 8.71 (s. 2H), 8.77 (s, 1H),
8.83 (s, 1H), 8.87
(s, 1H), 8.91 (d, J=2Hz, 1H), 9.59 (s, 1H), 13.68 (brs, 1H), 14.02 (s, 1H);
ESIMS found
C271123N702 m/z 478.3 (M+H).
0 NH
\ NH
\N
321
[005501 N-(5-(3 -(7-(Furan-3 -y1)-3H-imidazo [4,5 -c] pyri din-2 -y1)-1H-
indazol-5-
yl)pyri din-3 -y1)-2-phenylacetamide 321
[00551] Beige solid (12.6 mg, 7.3% yield). 111 NMR (DMSO-d6, 500 MHz) 6
ppm 3.76 (s, 2H), 7.27 (t, 1H), 7.30-7.40 (m, 4H), 7.45 (s, 1H), 7.77 (s,
1H), 7.84
(ABq, J=11.5Hz, 2H), 8.57 (s, 1H), 8.71 (s, 2H), 8.76 (s, 2H), 8.79 (s, 1H),
8.83 (s, 1H),
10.58 (s, 1H), 13.65 (s, 1H), 14.02 (s, 1H); ESIMS found C301-121N702 m/z
512.1 (M+H).
0 NH
N\ NH
N
\N
329
[00552] N-(5 -(3 -(7-(Furan-3 -y1)-31-1-imidazo14,5-c]pyridin-2-y1)-1H-indazol-
5-
yl)pyridin-3 -yl)pentanamide 329
1005531 Brown solid (70.0 mg, 0.15 mmol, 7.3% yield). 1-11 NMR (DMSO-d6,
500 MIIz) 6 ppm 0.92 (t, J=7.5Hz, 31-1), 1.37 (sex, J=7.5Hz, 2H), 1.63 (quin,
2H), 2.41 (t, J=7.5Hz, 2H), 7.49 (brs, 1H), 7.82-7.93 (m, 3H), 8.60 (s, 1H),
8.70 (s, 1H),
8.73 (s, 1H), 8.82 (s, 2H), 8.88 (s, 1H), 8.96 (brs, 1H), 10.30 (s, 1H), 14.25
(s, 1H);
ESIMS found C27H23N702 m/z 478.3 (M+H).
136

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0 NH
N\ NH
NI
\ N
330
[00554] N-(5-(3-(7-(Furan-3-y1)-3H-imidazo [4,5-e]pyridin-2-y1)-1H-indazol-5-
yl)pyridin-3-y0cyclopropaneearboxamide 330
[00555] Light brown solid (10.6 mg, 4.2% yield). 11-1 NMR (DMSO-d6, 500
MHz) 6 ppm 0.82-0.86 (m, 4H), 1.86 (quin, J=5.5Hz, 1H), 7.49 (brs, 1H), 7.84-
7.92 (m,
3H), 8.64 (brs, 1H), 8.71 (d, J=7.5Hz, 211), 8.83 (d, J=9Hz, 211), 8.89 (s,
1H), 8.98 (brs,
1H), 10.64 (s, 1H), 14.28 (s, 1H); ESIMS found C26H19N702 m/z 461.9 (M+H).
0,_ N
1
0 NH
N\ NH
N
\N
333
[00556] N-(5-(3-(7-(Furan-3-y1)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-indazol-5-
yl)pyridin-3-yl)eyelohexaneearboxamide 333
[00557] Brown solid (9.7 mg, 3.8% yield). 11-1 NMR (DMSO-d6, 500 MHz) 8
ppm 1.14-1.36 (m, 311), 1.46 (dq, J=12.5Hz, J=2.5Hz, 2H), 1.49 (dq, J=12.5Hz,
J=2.5Hz,
2H), 1.67 (d, J= 12.514z, 1H), 1.79 (d, J=13Hz, 1H), 1.89 (d, J=12Hz, 211),
2.00 (d,
J=10Hz, 2H), 7.44 (brs, 1H), 7.80-7.87 (m, 3H), 8.57 (brs, 1H), 8.64-8.86 (m,
7H), 10.20
(s, 111), 13.75 (brs, 1H), 14.04 (s, 1H); ESIMS found C29H25N702 m/z 504.3 (M-
1-1-1).
N
cAks/
N\ NH
\ N
N/
137

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336
[00558] 2-(5-(5-((3 ,3-Difluoropyrrolidin-1 -yl)methyl)pyridin-3-y1)-1H-
indazo 1-3-y0-7-(3-fluoropheny1)-3 H-imidazo [4,5 -c]pyridine 336
[00559] Light brown solid (71.2 mg, 82.5% yield). 11.1 NMR (DMSO-d6, 500
MHz) 6 ppm 2.26 (sep, J=7Hz, 2H), 2.76 (t, J=7Hz, 2H), 2.95 (t, J=13Hz, 2H),
3.79 (s,
2H), 7.30 (dt, J=8.5Hz, õI=2Hz, 1H), 7.60 (q, J=7.5Hz, 1H), 7.85 (d, 1=9Hz,
1H), 7.91 (d,
1=8.5Hz, 1H), 8.06 (s, 1H), 8.22 (d, 111), 8.42
(d, 1-11.5Hz, 11-1), 8.57 (s, 1H),
8.76 (s, 1H), 8.87 (s, 1H), 8.89 (s, 1H), 8.93 (d, 1=2Hz, 1H), 13.77 (s, 1H),
14.03 (s, 1H);
ESIMS found C29H22F3N7 m/z 526.2 (M+H).
zr4
N
cõ:\N
N\ NH 'N
\ N
339
[00560] 245 -(5 -((3,3 -Difluoropyrrolidin-1-yl)methyl)pyridin-3-y1)-1H-
indazol-3-y1)-7-(pyridin-3-y1)-3H-imidazo[4,5-c]pyridine 339
[00561] Brown solid (67.2 mg, 87.2% yield). 11-1 NMR (DMSO-d6, 500 MHz)
6 ppm 2.27 (sep, 1=7Hz, 2H), 2.79 (t, 1=7Hz, 2H), 2.98 (t, 1=13Hz, 2H), 3.83
(s, 2H),
7.60 (dd, 1=7.5, 1=4.5Hz, 1H), 7.84 (d, 1=8.5Hz, 1H), 7.92 (d, 1=8.5Hz, 1H),
8.08 (s,
1H), 8.57 (s, 1H), 8.67 (d, J-4Hz, 1H), 8.75 (brs, 2H), 8.89 (s, 2H), 8.93 (s,
1H), 9.59 (s,
1H), 13.79 (s, 1H), 14.02 (s, 1H); ESIMS found C28H22F2N8 m/z 509.3 (M+H).
ON N
N )NH
N
\ N
fki
342
[00562] 245454(3 ,3 -Difluoropyrro lidin-1 -y 1)methyl)pyridin-3-y1)-1H-
indazol-3-y1)-7-(pi peridin- 1-y1)-3H-imidazo [4,5-e]pyridine 342
138

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[00563] Brown solid (50.4 mg, 42.1% yield). 1H NMR (DMSO-d6, 500 MHz)
6 ppm 1.60 (brs, 6H), 2.28 (sep, J=7Hz, 2H), 2.78 (t, J=7Hz, 2H), 2.96 (t, J-
13Hz, 2H),
3.42 (brs, 1H), 3.48 (brs, 3H), 3.80 (s, 2H), 6.67 (s, 1H), 7.76-7.86 (m, 21-
1), 8.06 (s, 1H),
8.54 (s, 1H), 8.62 (s, 111), 8.70 (s, 1H), 8.86 (d, J=2Hz, 1H), 12.88 (s,
111), 13.79 (s, 1H);
ESIMS found C28H28F2N8m/z 515.4 (M+H).
\ / N
N \ NH
N
N
14/
346
[00564] 245 -(5 -((3,3 -Difluoropyrrolidin-1 -yl)methyl)pyridin-3-y1)-
1H-
indazol-3 -y1)-7-(thiophen-3-y1)-3H-imidazo [4,5-c]pyridine 346
[00565] Brown solid (73.9 mg, 96.8% yield). 1H NMR (DMSO-d6, 500 MHz)
6 ppm 2.28 (sep, J=7Hz, 2H), 2.79 (t, J.----7Hz, 2H), 2.98 (t, J--13Hz, 2H),
3.82 (s, 21I),
7.75 (dd, J5Hz, J=3Hz, 111), 7.85 (d, J=9Hz, 1H), 7.92 (d, J=8.5Hz, 111), 8.12
(s, 111),
8.20 (d, J-4.5Hz, 111), 8.57 (s, 1H), 8.79 (s, 2H), 8.82 (s, 1H), 8.93 (s,
111), 8.96 (s, 111),
13.69 (s, 1H), 14.01 (s, 1H); ESIMS found C271121F2N7S m/z 514.4 (M+H).
HN
CNH F
NH
349
[00566] N-(5-(3 -(7-(3 -(2 -(D imethyl amino)ethyl amino)-5 -fluoropheny1)-31-
1 -
imidazo [4,5-c]pyridin-2-y1)- 111-indazol-5 -yOpyridin-3 -y1)-3 -
methylbutanamide 349
[00567] Light brown solid (17.8 mg, 0.03 mmol, 50.7% yield). 1H NMR
(DMSO-d6, 500 MHz) 6 ppm 0.97 (d, J=6.5Hz, 6H), 2.09 (s, 711), 2.26 (d, J=7Hz,
2H),
2.31 (brs, 2H), 3.11 (t, J=6Hz, 211), 5.79 (s, 1H), 6.44 (d, J=11Hz, Hi), 7.37
(s, 1H), 7.41
(d, J.-9.5Hz, 1H), 7.77 (d, J=9Hz, 111), 7.85 (d, J=8.511z, 1H), 8.36 (s, 1H),
8.63 (s, 2H),
139

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8.83 (s, 2H), 10.19 (s, 1H), 13.68 (brs, 1H), 14.01 (s, 111); ESIMS found C331-
134FN90 m/z
592.3 (M+H).
H
0 NH F
N\ NH
N
\N
373
[00568] N-(5-(3 -(743 -Fluoro-5-(methylsulfonami dometbyl)pheny1)-3H-
imidazo[4,5-c]pyridin-2-y1)-1H-indazol-5-yl)pyridin-3 -y1)-3 -
methylbutanarnide 373
[00569] Light brown solid (13.8 mg, 0.023 mmol, 20.9% yield). 11-1 NMR
(DMSO-d6, 500 MHz) 6 ppm 0.97 (d, J=6.5Hz, 6H), 2.11 (non, /-7.5Hz, 1H), 2.27
(d,
J=7Hz, 2H), 2.89 (s, 311), 4.29 (d, J=6Hz, 2E1), 7.24 (d, J-8.5Hz, 1H), 7.71
(t, J=6Hz,
1H), 7.80 (d, J=9Hz, 111), 7.87 (d, J=8.5Hz, 1H), 8.12 (s, 111), 8.39 (d,
J=10.511z, 1H),
8.44 (s, 111), 8.67 (s, 1H), 8.77 (s, 1H), 8.78 (s, 1H), 8.85 (s, 1H), 8.88
(s, 111), 10.20 (s,
11-I), 13.80 (s, 1H), 14.05 (s, 1H); ESIMS found C311-129FN803S m/z 613.1
(M+H).
0NH / N\
N \
\N
14/
397
[00570] 3 -Methyl-N-(5-(3 -(7-(thiophen-2-y1)-3 H-imidazo [4,5-c]pyridin-2-y1)-
1H-indazol-5-yOpyridin-3-yl)butanamide 397
[00571] Light brown solid (79.8 mg, 0.16 mmol, 62.2% yield). 1-11 NMR
(DMSO-do, 500 MHz) 6 ppm 0.98 (d, J-6.5Hz, 6H), 2.15 (non, J=7Hz, 114), 2.31
(d,
J=7.511z, 21-1), 7.26 (dd, J=5Hz, J--3.5Hz, 1H), 7.66 (d, J=5Hz, 1H), 7.86 (s,
2H), 8.23
(brs, 1H), 8.61 (s, 1H), 8.70 (d, J=1.5Hz, 1H), 8.73 (d, J=2Hz, 111), 8.77 (s,
1H), 8.81 (s,
1H), 9.01 (s, 1H), 10.28 (s, 1H), 13.77 (brs, 1H), 14.04 (s, 1H); ESIMS found
C271123N70S inlz 494.1 (M+H).
140

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Example 2.
[00572j The above synthesized compounds were screened using the assay
procedure for Writ activity described below.
[00573] Reporter cell lines can be generated by stably transducing cells of
cancer cell lines (e.g., colon cancer) with a lentiviral construct that
include a writ-
responsive promoter driving expression of the firefly luciferase gene.
[00574] Lentiviral constructs can be made in which the SP5 promoter, a
promoter having eight TCF/LEF binding sites derived from the SP5 promoter, is
linked
upstream of the firefly luciferase gene. The lentiviral constructs can also
include a
hygromycin resistance gene as a selectable marker. The SP5 promoter construct
can be
used to transduce SW480 cells, a colon cancer cell line having a mutated APC
gene that
generates a truncated APC protein, leading to de-regulated accumulation of13-
catenin. A
control cell line can be generated using another lentiviral construct
containing the
luciferase gene under the control of the SV40 promoter which does not require
13-catenin
for activation.
[00575] Cultured SW480 cells bearing a reporter construct can be distributed
at
approximately 10,000 cells per well into 384 well multiwell plates. Compounds
from a
small molecule compound library can then be added to the wells in half-log
dilutions
using a three micromolar top concentration. A series of control wells for each
cell type
receive only buffer and compound solvent. Twenty-four hours after the addition
of
compound, reporter activity for luciferases can be assayed, for example, by
addition of
the BrightGlo luminescence reagent (Promega) and the Victor3 plate reader
(Perkin
Elmer). Readings can be normalized to DMSO only treated cells, and normalized
activities can then be used in the IC50 calculations. Table 2 shows the
activity of selected
indazole analogs.
Table 2.
Wnt inhibition Wnt inhibition Wnt
inhibition
Compound Compound Compound
(11M) (ILLM) (NM)
1 0.14 - 0.15 111 0.006 280 0.021
2 0.125 - 0.146 124 0.001 283 0.008
3 0.083 - 0.179 127 0.014 286 0.569
4 0.013 - 0.040 136 0.035 289 0.002
141

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0.067 - 0.098 r 154 0.373 291 0.002
6 0.010 - 0.013 163 0.296 293 0.191
7 0.214 - 0.463 164 >6 295 0.003
9 0.4 - 0.63 170 7 301 0.069
,
0.0034 - 0.009 173 0.845 303 1
11 0.0035 - 0.065 174 0.003 304 0.003
12 0.006 - 0.008 177 , 0.002 311
0.058
0.010 -0.025 186 0.038 315 0.022
16 0.164 -0.200 199 0.311 319 0.005
_ 20 0.0014 - 0.0018 202 0.535 321 0.033
24 0.066 205 0.041 329 0.004
31 0.005 211 = 0.42 330 0.739
86 0.023 214 0.042 333 0.026
89 >10 217 0.039 336 0.055
90 0.012 247 0.002 339 0.039
91 0.002 252 _ 0.650 342 0.020
_ 94 0.011 257 0.095 346 0.002
97 0.001 260 0.315 349 0.022
99 >5 263 0.086 373 0.005
102 .004 268 >10 397 0.0001
104 0.007 274 >10
107 0.052 275 0.141
Example 3.
[00576] Preparation of a parenteral suspension with a compound of Formula I
for the treatment of bone/cartilage diseases.
Table 3. Approximate solubility of a compound of Formula I
Media Solubility (tg/mL)
0.01N HC1 5
0.1 N HC1 150
lOmM PBS pH 7.4 <0.05
PBS/0.5%CMC/0.05%Tween80 0.3
PEG 400 8500
Propylene glycol 3700
Et01-1 4500
Ethyl acetate 80
DCM 35
Captex 300 C8/C10 Triglyceride 50
[00577] Dynamic vapor sorption shows up to 17.2% water is absorbed,
showing the hygroscopicity of a compound of Formula I.
142

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= 60412-4774
Table 4. Differential scanning calorimetry results for a compound of Formula I
Sample Dehydration Polymorphic change Melting
Anhydrous API N/A 282.7 C & 17.4 J/g 361 C &
128.3 J/g
Hydrated API 101 C & 309 J/g 283.7 C& 13.6 J/g 363 C&
117.9 J/g
[00578] Preparation of a 220 fig/mT suspension in 0.5% CMC/0.05% TweenTm 80
im
begins by dispensing 597 g 1 g of Gibco 1X PBS into the 1 L glass bottle.
Using a 1
mL sterile syringe, measure 0.3 mL of Tweenm80. In a weigh boat, weigh out 3 g
0.1 g
TM
of Carboxymethyl Cellulose 7LXF PH (CMC). Start mixing the Tween80/PBS
solution
and slowly sprinkle the CMC into the 1 L bottle containing the PBS/TweeTMn
mixture
(increase mixing speed as necessary). Once visually dispersed and the polymer
is
hydrated, start heating the container on a heating plate to promote phase
inversion
(turbidity). Once the solution is cool to the touch, filter NLT 120 mL into
the 250 mL
glass bottle. Weigh 27 mg of a compound of Formula I and suspend by mixing
with the
aid of 120 g of the sterile filtered CMC/Tweenim solution. Fill 2 mL schott
glass vials and
13 mm Flurotec coated stoppers (West Pharma) and autoclave the vials at 260 F
for NLT
25 minutes. Particle size measurement (Table 4) was performed after
autoclaving using a
Horiba L-950.
Table 5.
D(v, 0.1) D(v, 0.5) D(v, 0.9)
220 g/mL suspension (autoclaved) 1.5 um 2.811m 4.911m
Table 6.
Osmolality pH Viscosity % purity Concentration
(HPLC) (HPLC)
220 g/mL suspension 308 mOsm/kg 7.3 2.3 cP 99.0
2261g/mL
(autoclaved)
Example 4.
[00579] Preparation of a parenteral preparation with a compound of Formula I.
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[00580] Weigh 10 mg of a compound of Formula I (or its salt) and dissolve
with the aid of 10 mL of propylene glycol (USP grade), using aseptic
techniques, sterile
filter the solution using a millex GP syringe filter into a sterile glass
(type II) container.
Before parenteral administration, add 10mL of the above solution in propylene
glycol to a
vial containing 90 mL of sterile water, mix well.
Example 5.
[00581] Preparation of a suspension for intravitreal injection with a compound
of Formula I.
100582] Weigh 10 mg of micronized compound of Formula I (median particle
size of 5 pm) an added slowly while mixing to 100 mL of solution of 0.5%
carboxymethyl cellulose (AqualonTM 7LXF) and 0.05% TweenTm 80 HP-LQ-MII
(CrodaTm) dissolved in PBS (GibeoTm, pH 7.4). The final suspension is loaded
into 2 mL
glass vials and terminally sterilized by autoclaving.
[00583] It is also contemplated to heat sterilize the micronized compound of
Formula I and aseptic mixing with the sterile filtered solution of 0.5%
earboxymethyl
cellulose (AqualonTM 7LXF) and 0.05% TweenTm 80 HP-LQ-MH (CrodaTM) dissolved
in
PBS (GibcoTM, pH 7.4).
[00584] Administration was performed using a 30G needle and a volume of
approximately 50 uL for intravitreal injection in rabbits, the presence of the
drug in the
back of the eye (choroid/retina) was confirmed by LC/MS analysis after
extraction using
acetonitrile/ foimic acid solution.
Example 6.
[00585] Composition for intratympanic injection with a compound of Formula
I.
[00586] Weigh 10 mg of a compound of Formula I and dissolve with the aid of
100 mL of propylene glycol (USP grade), using aseptic techniques, sterile
filter the
solution using a millex GP syringe filter into a sterile glass (type II)
container. Before
parenteral administration, add 10 mL of the above solution in propylene glycol
to a vial
containing 90 mL of sterile water, mix well.
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[00587] Administration is performed using a 25G needle and a volume of
approximately 200 L for intratympanic injection targeting the round window
membrane.
Example 7.
[00588] Preparation of a composition for pulmonary delivery with a compound
of Formula I for the treatment of pulmonary fibrosis.
[00589] Weigh 100 mg of a compound of Formula I (or its salt) an added
slowly while mixing to 100 mL of solution of 1.5% dextrose (or lactose) +
0.05%
tyloxapol. The final solution is sterile filter the solution using a millex GP
syringe filter.
[00590] Administration is performed using a jet nebulizer (Pan i LC plus) or
an
aerodose nebulizer.
[00591] C57/B16 mice were dosed for 30 minutes via a nose only chamber (CH
technology) at a flow rate of 15 LPM, particle size distribution and dose was
measured by
a 7 stage impactor (1 LPM) placed in one of the ports. A median aerosol
particle size of
1.2 um with a GSD of 1.8 um was obtained and a dosing rate of 1.8
uM/min/mouse.
Table 7.
Concentrations of a compound of Formula I in Mice (C57/B16)
Inhalation Conc. (ng/mL)
Time Point (h) Plasma Lung Ratio
0.25 188 12600 67
2 132 7510 57
6 29.9 5225 175
23 453 2945 7
[00592] A diluted formulation of 0.5 mg/mL of compound of Formula I was
nebulized for 10 and 30 minutes to C57/b16 mice (animals with bleomycin
induced
pulmonary fibrosis via the administration of bleomycin via intratracheal
administration),
the compound of Formula I was delivered via a nose only chamber (CH
technology) at a
flow rate of 20 LPM daily for 14 days. At the end of the 14 days, the animals
were tested
for MMP-7 levels and the lungs were scored using the Ashcroft scoring system
to
evaluate pulmonary fibrosis.
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Table 8.
Treatment Ashcroft Scoring MMP-7 levels
(ng/mL)
PBS/no dose 0.25 10
Bleomycin/vehicle 3.04 13.6
Bleomycin/ 10 min aerosol
3.52 10.7
of a compound Formula I
Bleomycin/ 30 min aerosol
2.08 9.4
of a compound Formula I
Example 8.
[00593] Preparation of a suspension of drug-eluting material with a compound
of Formula I.
[00594] Solution 1 (PLGA containing active): Weigh 425mg of PLGA 50:50
(PLGA 0.55-0.75, Lactel B6010-2P) + 4.5 mg of a compound of Formula I + 4mL of
dichloromethane, mix well to dissolve.
[00595] Solution 2 (1% PVA solution): Add 40 mL of DI water, then add 413
mg of polyvinyl alcohol (Sigma 87-89% hydrolyzed, PN 363170-25), mix to
dissolve
then sterile filter through a 0.22 j PES syringe filter (Millipore Millex GP).
[00596] PLGA microparticle formation: Add 20 mL of solution 2 into a clean
sterile container, while mixing (high speed mixing) slowly add the entire 4 mL
of
solution 1 to solution 2.
[00597] The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive or open-
ended and does
not exclude additional, unrecited elements or method steps.
146

Representative Drawing